1
1
Preprint
2
Review
3
Calcium
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Mechanisms and regulation
transport
in
strongly
calcifying
laying
birds:
5
6
7
Arie Bar1
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Institute of Animal Science, ARO, the Volcani Ctr., Bet Dagan, Israel
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Running head: Calcium transport in laying birds
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Published in: Comparative Biochemistry and Physiology, Part A: Molecular & Integrative
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Physiology, (2009) 152: 447-569.
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For the printed version please link to:
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http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&
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list_uids=19118637
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1
Retired; Institute of Animal Science, ARO, the Volcani Ctr., Bet Dagan 50250, Israel;
E-mail: ariebar@agri.gov.il
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ABSTRACT
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Birds that lay long clutches (series of eggs laid sequentially before a “pause day”), among
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them the high-producing, strongly-calcifying Gallus domesticus (domestic hen) and Coturnix
28
coturnix japonica (Japanese quail), transfer about 10% of their total body calcium daily. They
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appear, therefore, to be the most efficient calcium-transporters, among vertebrates. Such
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intensive transport imposes severe demands on ionic calcium (Ca2+) homeostasis, and
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activates at least two extremely effective mechanisms for Ca2+ transfer from food and bone to
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the eggshell.
33
This review focuses on the development, action and regulation of the mechanisms
34
associated with paracellular and transcellular Ca2+ transport in the intestine and the eggshell
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gland (ESG); it also considers some of the proteins (calbindin, Ca2+ATPase, Na+/Ca2+
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exchange, epithelial calcium channels (TRPVs), osteopontin and carbonic anhydrase (CA))
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associated with this phenomenon. Calbindins are discussed in some detail, as they appear to
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be a major component of the transcellular transport system, and as only they have been
39
studied extensively in birds. The review aims to gather old and new knowledge, which could
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form a conceptual basis, albeit not a completely accepted one, for our understanding of the
41
mechanisms associated with this phenomenon.
42
In the intestine, the transcellular pathway appears to compensate for low Ca2+ intake, but
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in birds fed adequate calcium the major drive for calcium absorption remains the
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electrochemical potential difference (ECPD) that facilitates paracellular transport. However,
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the mechanisms involved in Ca2+ transport into the ESG lumen are not yet established. In the
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ESG, the presence of Ca2+-ATPase and calbindin-two components of the transcellular
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transport pathway–and the apparently uphill transport of Ca2+ support the idea that Ca2+ is
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transported via the transcellular pathway. However, the positive (plasma with respect to
49
mucosa) electrical potential difference (EPD) in the ESG, among other findings, indicates that
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there may be major alternative or complementary paracellular passive transport pathways.
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The available evidence hints that the flow from the gut to the ESG, which occurs during a
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relatively short period (11 to 14 h out the 24- to 25.5-h egg cycle), is primarily driven by
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carbonic anhydrase (CA) activity in the ESG, which results in high HCO3- content that, in
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turn, “sucks out” Ca2+ from the intestinal lumen via the blood and ESG cells, and deposits it
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in the shell crystals. The increased CA activity appears to be dependent on energy input,
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whereas it seems most likely that the Ca2+ movement is secondary, that it utilizes passive
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paracellular routes that fluctuate in accordance with the appearance of the energy-dependent
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CA activity, and that the level of Ca2+ movement mimics that of the CA activity. The on-off
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signals for the overall phenomenon have not yet been identified. They appear to be associated
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with the circadian cycle of gonadal hormones, coupled with the egg cycle: it is most likely
3
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that progesterone acts as the “off” signal, and that the “on” signal is provided by the
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combined effect of an as-yet undefined endocrine factor associated with ovulation and with
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the mechanical strain that results from “egg white” formation and “plumping”. This strain
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may initially trigger the formation of the mammillae and the seeding of shell calcium crystals
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in the isthmus, and thereafter initiate the formation of the shell in the ESG.
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Keywords: ATPase, Calbindin, Calcium, Carbonic anhydrase, Eggshell gland, Epithelial
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calcium channels, Gonadal hormones, Intestine, Pump, Paracellular, Transcellular, Transport,
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Vitamin D, Uterus
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Contents
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1. Introduction
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2. Proteins involved in calcium transport
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2.1. Epithelial calcium channels (TRPVs)
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2.2. Calbindins
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2.3. Plasma membrane calcium-ATPase (Ca2+-ATPase or PMCA)
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78
2.4. Na+/Ca2+ exchange
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2.5. Carbonic anhydrase
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2.6. Osteopontin
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3. Intestinal calcium absorption in the laying bird
3.1. Overall aspects and methodologies
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3.1.1. Methodologies
x
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3.1.2. Site of absorption
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85
3.1.3. Intestinal absorption of Ca2+ in birds, as influenced by nutrition
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or physiological status
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3.2. Mechanisms of intestinal absorption
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3.3. Absorption of Ca2+ in the laying bird
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3.3.1. Development of absorption capability
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3.3.2. Circadian calcium absorption
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3.3.3. Bone–the other source of shell calcium
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4. Eggshell transport of calcium
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4.1. Early studies on the evaluation of the capability and regulation of calcium
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transport in the eggshell gland
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4.2. Eggshell gland cyclic functionality
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4.3. Shell-gland-specific proteins
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4.4. Mechanism of calcium transport in the eggshell gland
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5. Conclusions and speculations
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Acknowledgment
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References
47
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101
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102
1. Introduction
103
A unique characteristic of mammalian reproduction is the ability to maintain a most
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appropriate and protective environment for embryo development inside the uterus. Other
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vertebrate species, including the thermo-regulated avian species, lack this evolutionary
106
advantage; at an earlier stage of evolution they developed a semi-protected milieu, the egg,
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which fulfils most embryo needs, apart from the thermo-regulated environment. The eggshell
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isolates the internal milieu from external threats, such as dryness or microorganism
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penetration, and does so quite adequately in nature. However, modern industrialization and
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environmental contamination exposes avian species to new, "human-made" threats, many of
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which impair shell integrity, which arouses our renewed interest in the biology of eggshell
112
formation. The fact that human population world-wide consumes about 1012 eggs per year
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(64.4 million metric tons in 2005 according to the FAO) adds an economic aspect to the
114
subject.
115
Although many domesticated birds lost some of the typical characteristics of wild birds,
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such as flying, migration capability, or seasonal breeding, they retained other characteristics,
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such as photosensitivity, circadian rhythms of egg formation, and sequential patterns of
118
laying eggs (clutch). These characteristics, together with the high reproduction rate of the
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domestic hen (Gallus domesticus) and its economic importance, made this species the
120
commonest model for studying shell formation. Other domesticated, or semi-domesticated,
121
species, such as the duck (Anas platyrhynchos) (Benoit et al. 1944; Lundholm 1991)2,
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turkey (Meleagris gallopova) (Musser et al. 1977), ostrich (Struthio camelus) (Holm et al.
123
2000), or Japanese quail (Coturnix coturnix japonica), (Bar et al. 1976a; Bar et al. 1976b;
124
Kenny 1976; Musser et al. 1977; Striem et al. 1991; Holm et al. 2001) have also been
125
extensively studied. Among these species the quail appears to be the most similar to the
126
domestic hen with regard to productivity, egg cycle length, shell formation, calcium
127
homeostasis, and cholecalciferol (vitamin D3) metabolism and expression (Tables 1, 2), but
128
not with regard to ovulation time. Because they are small and oviposit and ovulate in the
129
afternoon, and their shell calcification occurs during daylight hours, quail has become an
130
attractive and widely used bird for research on shell calcification, vitamin D metabolism and
131
calcium homeostasis The latter is controlled by three calcium-regulating hormones
132
(calcitropic): parathyroid hormone (PTH; reviewed in (Ingleton 2002; Dack, 2000; Talmage
133
and Mobley, 2008; Potts 2005)), the hormonal form of vitamin D3–the 1,25 dihydroxyvitamin
134
D3 (1,25(OH)2D3; reviewed in (Hurwitz 1992; Norman 1995; Soares et al. 1995; Bouillon et
22
Only few of the relevant reviews or original articles are cited. Efforts have been done to cite in most cases the most recent
reviews and the earlier original papers. In some cases are cited other (more recent, more relevant or more comprehensive)
publications.
6
135
al. 1997; Henry 1997; Pike and Shevde, 2005; Wasserman 2005; Haussler et al. 1998; Jones
136
et al. 1998; Whitehead 1998; Brown et al. 1999; Edwards 2000; Holick 2003; DeLuca 2004;
137
Dusso et al. 2005; Wasserman 2005; Norman 2006; Christakos et al. 2007; Bar 2008; Khanal
138
et al. 2008, Perez et al. 2008; Perez et al. 2008)) and calcitonin (reviewed in (Silverman 2003;
139
Huang et al. 2006; Ramasamy 2006)).
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141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
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162
163
164
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Table 1. Some variables of egg laying in the fowl and quail
_____________________________________________________________________________________________
Variable
Fowl
Quail
Reference
_____________________________________________________________________________________________
Body weight at production onset, kg
Egg cycle length3, h
Egg production, eggs per 348 d4
Egg weight, (age of 13-14 m), g
Shell Ca2+, g
1.527±0.2301
23 to 28
324±28
67.0±5.3
2.30±0.22
Oviposition, h post lights turned off 5 12 to16
Peak of progesterone, h prior
ovulation
6 to 2
0.110 to 2022
24 to 26
309±905
10.3±0.5
0.284±0.031
18 to 26
6 to 2
(Bar et al. 1981b; Bar et al. 1998;
Minvielle et al. 2000)
(Kobayashi et al. 1981; Etches 1990;
Sonoda et al. 1997)
(Bar et al. 1998; Minvielle et al. 2000)
(Bar et al. 1976b; Bar et al. 1998)
(Bar et al. 1976b; Bar et al. 1996)
(Kobayashi et al. 1981; Etches 1990;
Sonoda et al. 1997)
(Furr et al. 1973; Haynes et al. 1973;
Lague et al. 1975; Shahabi et al. 1975;
Doi et al. 1980; Johnson et al. 1980;
Gulati et al. 1981; Kamar et al. 1982;
Nys et al. 1986a; Vanmontfort et al.
1994; Braw-Tal et al. 2004)
_____________________________________________________________________________________________
1
Mean ± SD
2
Range for several different breeds
3
Birds maintained under 14L:10D regime (L = light on, D = light off). In 14-month-old fowls maintained at
16L:8D cycle length (±SD) was 24.3 ± 0.6 h (Bar et al., unpublished results)
4
During the age ranges of 153 to 500 and 40 to 397 days, respectively, in breed selected for egg laying.
5
Birds maintained under 14L:10D regime (L = light on, D = light off). In fowls maintained under 16L:8D
regime, cycle length (±SD) was 23.6 ± 1.4 h; 73% of the eggs were oviposited within 11 to 15 h following light
off (Bar et al., unpublished results)
7
170
171
Table 2. Selected data on the effect of egg laying (a) and shell calcification (b) in the female
fowl (Gallus domesticus) and quail (Coturnix coturnix japonica) 1
172
173
A. Effect of egg laying
_______________________________________________________________________
174
175
176
Variable
177
________________________________________________________________________
178
179
Plasma calcium , mM
180
181
Plasma 1,25(OH)2D3, nM
182
183
Jejunal (upper villus) VDR4,
184
185
186
187
Duodenal calbindin, mg/g
188
189
Ca2+ absorption5, % of intake
190
191
192
193
ESG6 VDR4, pmol/g
1.40±0.05 2.44±0.20
ESG6 calbindin, mg/g
0.17±0.13 1.14+0.08
194
________________________________________________________________________
195
Fowl
Immature
Quail
Laying3
pullet
2.78±0.1
Immature
.
References2
Laying3
pullet
6.82±0.62
2.7±0.15
6.15±0.32
(Bar et al. 1978b;
Singh et al. 1986)
0.11±0.01
0.61±0.08
0.42±0.07
1.38±0.15
(Bar et al. 1981b;
Nys et al. 1989)
abundance measures
4.3±0.5
0.34±0.09
13.4±1.6
2.16±0.19
(Wu et al. 1993)
0.44±0.16
2.06±0.20
(Bar et al. 1975a;
Bar et al. 1976a;
Montecuccoli et al.
1977b)
21.3±2.6
50.1±6.23
21.3±2.6
63.9±3.8
(Bar et al. 1978a;
Cohen et al. 1978)
(Striem 1990)
1.10±0.09
1.70±0.08
(Bar et al. 1975a;
Montecuccoli et al.
1977b)
8
196
197
198
199
200
201
202
203
204
205
206
207
208
209
210
211
212
213
214
215
216
217
218
219
220
221
222
223
224
225
226
227
228
229
230
B. Effect of shell calcification on laying birds fed laying diets (adequate calcium)
_______________________________________________________________________
231
232
233
234
235
236
237
238
239
240
241
242
243
244
245
________________________________________________________________________
Variable
Fowl
6
ESG
inactivity
Quail
Shell
calcification
ESG
inactivity
References2
.
Shell
calcification
________________________________________________________________________
Plasma calcium , mM
5.12±0.2
5.89±0.37
6.9±0.2
6.7±0.17
Plasma Ca+2, mM
1.45±0.06
1.31±0.047
0.98±0.088
0.74±0.048 (Kaetzel et al. 1985;
Singh et al. 1986)
1.15±0.05
1.04±0.03 (Dacke et al. 1973)
Plasma PTH, pg/ml
Plasma 1,25(OH)2D3, nM
Jejunal VDR4 mRNA,
% of 1 h pre ovulation
0.55±0.10
(Singh et al. 1986)
5.95±0.61
0.70±0.07
0.78±0.1
0.53±0.02
0.68±0.05
91
(Bar et al. 1976b; Bar
et al. 1996)
0.53±0.12
8
8
0.68± 0.17 (Bar et al. 1984b;
Kaetzel et al. 1985)
(Nys et al. 1992a)
90
(Ieda et al. 1995)
Duodenal calbindin mRNA9,
fmol/ng RNA
Duodenal calbindin, mg/g
276±12
2.62±0.13
Ca2+ absorption5, % of intake 38.0±8.6
ESG6 VDR4 mRNA,
% of 1 h pre ovulation
254±33
2.16±0.19
59.9±5.3
44
400
fmol/ng RNA
48±21
248±.15
ng/g tissue
22±4
514±77
238±43
1.85±0.25
17.8±4.3
404±68
(Striem et al. 1991;
Bar et al. 1992a)
2.06±0.20 (Bar et al. 1975a; Bar
et
al.
1976a;
Montecuccoli et al.
1977b)
63.9±3.8
(Bar et al. 1976a;
Cohen et al. 1978)
(Ieda et al. 1995)
ESG6 calbindin mRNA9
ESG calbindin, mg/g
1
1.20±0.08 1.14+0.08
41±10
509±26
(Striem et al. 1991; Bar et al.
1992a)
(Nys et al. 1989)
2.88±0.13
2.24±0.15
(Bar et al. 1975a; Bar et al.
1976b; Bar et al. 1978b)
The table is intended to bring together quantitative and comparative data. Many other studies, but not all, are
mentioned in the text and in the list of references.
2
Respectively.
3
During period of shell calcification.
4
Vitamin D receptor.
5
Intestinal absorption capability of laying hens during shell calcification reaches in some studies much higher
(Hurwitz et al. 1973a).
6
Eggshell gland (uterus).
7
Other publications (data given as figures) indicated for a more pronounced differences between calcifying and not
calcifying fowls (Nys et al. 1986a; Frost et al. 1990).
8
Calculated from the original graphical presentation.
9
Based on intestinal level at 1 h pre ovulation.
10
Original data were presented as figures.
9
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Egg laying and shell calcification impose severe extra demands on Ca2+ homeostasis,
247
since shell formation requires several times as much calcium as the amount present in the
248
extra-cellular pool. In the high-laying-rate domestic hen and quail, 2 to 3 g (about 10% of the
249
total body calcium) and approximately 0.3 g, respectively, of Ca2+ is secreted daily during the
250
relatively short period (11-14) h out of the 24-25.5 h cycle) of intensive shell calcification.
251
This complicates the conceptual model of homeostasis that fits non-laying animals (reviewed
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in (Hurwitz 1990; Miller 1992; Hurwitz 1996; Sasayama 1999; Bar 2008)) by introducing an
253
additional Ca2+ pathway: its withdrawal through the uterus (eggshell gland; ESG). The last is
254
a process that appears not to be controlled by the three calcium-regulating hormones, or at
255
least to be controlled differently from Ca2+ transport in the intestine, bone and kidney
256
(reviewed in (Bar 2008)).
257
The steady state of calcium metabolism in the non-laying bird is challenged, first through
258
the initiation of gonadal activity during maturation prior to egg laying, and then by the
259
increased demands for shell Ca2+ during the egg-laying phase (reviewed in (Dacke 2000; Bar
260
2008)). During maturation the secretion and activity of gonadal hormones create increased
261
Ca2+ requirements, to support new medullary bone (MB) formation and to saturate the
262
estrogen-dependent-plasma-calcium-binding proteins formed in the liver (reviewed in
263
(Griffin 1992; Walzem 1996; Davis 1997; Walzem et al. 1999) and others).
264
The daily Ca2+ intake of the laying hen appears to be 4.2 to 4.6 g/d (based on daily feed
265
intake of approximately 115 g/d and the recommended calcium content of 3.6 to 4.0%). At
266
zero nutritional balance for calcium, and under the theoretical conditions–which are not
267
fulfilled in nature–of constant dietary inflow and shell-deposition outflow of Ca2+, the net rate
268
of dietary Ca2+ absorption in the laying domestic hen should be about 50%. In fact, the actual
269
rate of absorption is greater, because the flow of Ca2+ from the intestine to the plasma occurs
270
mainly when the gut contains calcium derived from the diet, which occurs only during
271
daylight and the early hours of darkness, because eating ceases after sunset or after switching
272
off of the artificial lighting. According to the rate of passage of feed through it (Hurwitz et al.
273
1966b), the intestinal lumen became almost completely empty of calcium 4 to 5 h after the
274
end of the feeding period or after "lights-out". Since intensive shell calcification in the
275
commercial fowl occurs between 9 and 22 h after ovulation, i.e., -1 to 13 h after lights-out;
276
(Table 1), a major proportion of the shell Ca2+ is deposited while the intestine lacks dietary
277
calcium. In order to overcome the lack of synchronization between the circadian availability
278
of dietary calcium and the circadian deposition of calcium into the eggshell, two mechanisms
279
were promoted: (a) enhancement of net absorption of Ca2+ during the early dark period, when
280
feed is still present in the gut; and (b) the activation of an efficient process of bone resorption
281
during the second half of the dark period. Incomplete (Bar et al. 1988; Clunies et al. 1993)
10
282
restoration of the circadian bone loss of Ca2+ in birds laying sequentially long clutches, occurs
283
during the subsequent daylight period, when the intestinal absorption of Ca2+ is enabled by
284
the renewal of calcium intake in the feed. Thus, the source of the daily deposition of shell
285
Ca2+, both direct and indirect (bone mediated) in birds with long clutches, must be the
286
intestine.
287
2. Proteins involved in calcium transport
288
At least four groups of proteins are considered to be involved in calcium transport, namely:
289
calbindins; plasma membrane calcium-ATPases (Ca2+ATPases or PMCAs); Na+/Ca2+
290
exchangers (NCXs); and epithelial calcium channels (TRPVs). Whereas these four groups of
291
proteins appear to be involved in transcellular transport (see 3.2) of Ca2+, a fifth group, which
292
includes the Tight Junction (TJ) proteins, is believed to be involved in paracellular transport.
293
At least two other groups of proteins are believed to be associated specifically with ESG
294
calcium transport: carbonic anhydrase (CA) and osteopontin (OPN). As some of these
295
proteins appear to be vitamin-D-dependent or -related proteins, their activity is facilitated by
296
another group of proteins, the nuclear vitamin D receptors (nVDR) and the membrane
297
bound/attached VDRs (mVDR). The nVDRs were extensively reviewed (Norman 1995;
298
Bouillon et al. 1997; Henry 1997; Pike and Shevde, 2005; Wasserman 2005; Haussler et al.
299
1998; Jones et al. 1998; Brown et al. 1999; Holick 2003; DeLuca 2004; Dusso et al. 2005;
300
Wasserman 2005; Norman 2006) and were specifically discussed with regard to theirs
301
relevance to the laying bird (Bar 2008). The mVDR and the TJ proteins (reviewed in
302
(Norman et al. 2002; Dusso et al. 2005; Norman 2006) and in (Schneeberger et al. 2004; Van
303
Itallie et al. 2006), respectively) were less studied and were not yet investigated with regard to
304
their relevance to the laying bird.
305
VDRs, TRPVs, and PMCAs were reviewed extensively (see 2.1, 2.3 and (Bar 2008)) and
306
theirs relevance to the laying bird was addressed recently (Bar 2008), therefore they are not
307
addressed or are only briefly discussed in the present review, in which more attention is paid
308
to NCXs and osteopontin, which were not discussed in the earlier review. As CAs appear to
309
be most important for ESG transport of Ca2+, they are discussed widely in the present review,
310
with regard to egg laying also. Special attention is given to avian calbindin as it is the only
311
calcium-transport-related protein that has been studied extensively in birds, because it is
312
considered to be an important component of the transcellular route of Ca2+ transport and
313
because it was used in many studies as a means of estimating Ca2+ absorption. This protein,
314
although widely discussed in an earlier review (Bar 2008) is discussed in the present one with
315
respect to some characteristics that were not addressed in the earlier review, its differential
316
regulation and its possible differential functionalities in the intestine and the ESG.
11
317
2.1. Epithelial calcium channels (TRPVs)
318
The TRP (Transient Receptor Potential) super-family of cation channels is widely
319
distributed in calcium-transporting tissues such as mammalian proximal intestine, kidney and
320
placenta (reviewed in: (Belkacemi et al. 2005; Hoenderop et al. 2005b; Niemeyer 2005; van
321
der Eerden et al. 2005; Lambers et al. 2006a; Venkatachalam et al. 2007 ; Bar 2008)). Briefly,
322
they comprise more than 27 proteins in six subfamilies. TRPV5 and TRPV6 are considered to
323
facilitate the entry of Ca2+ into the epithelial cells of the calcium-transporting organs. Their
324
gene expression in the mammalian intestine and kidney is regulated by 1,25 (OH)2D3 and the
325
genes encoding them have a VDRE (reviewed in (Belkacemi et al. 2005; Brown et al. 2005;
326
Hoenderop et al. 2005b)). Estrogens have a distinct, vitamin D-independent stimulating effect
327
at the genomic level of TRPV6 (reviewed in (Hoenderop et al. 2005a; van Abel et al. 2005));
328
they also affect renal TRPV5 (Van Cromphaut et al. 2003). The effect of estrogen on TRPV6
329
may be mediated by an estrogen-responsive element (ERE) that has been identified on the
330
promoter sequence of mouse TRPV6, but not on TRPV5 (Weber et al. 2001). The specific
331
role of TRPVs in the transport of Ca2+ in the laying-hen intestine and ESG has not yet been
332
studied.
333
2.2. Calbindins
334
This group of proteins, previously named CaBPs (Ca-binding proteins) was widely
335
reviewed (Gross et al. 1990; Heizmann et al. 1990; Thomasset 1997; Hemmingsen 2000;
336
Christakos et al. 2003; Choi et al. 2005; Christakos et al. 2005). Avian calbindin was recently
337
reviewed with regard to laying status and shell calcification ((Bar 2008) and in Bar, 2009, in
338
preparation).
339
Briefly: High concentrations of calbindins are found in tissues characterized by their
340
massive transport of Ca2+, such as intestine, kidney and avian ESG (Wasserman et al. 1966;
341
Taylor et al. 1967; Corradino et al. 1968). Lower concentrations of calbindins are found in
342
other tissues associated with Ca2+ homeostasis and metabolism; these include bone, tooth
343
cells and PT cells. These proteins are also found in tissues not directly associated with Ca2+
344
transport: the nervous tissues contain high concentrations; the pancreas and testes contain low
345
concentrations (reviewed in (Christakos et al. 2005). In the calcium-transporting tissues the
346
calbindins are considered to facilitate the movement of Ca2+ within the epithelial cells of the
347
calcium-transporting organs.
348
Recently it was also suggested (reviewed in (Lambers et al. 2006b; Christakos et al.
349
2007)) that calbindins may act as a buffer, by maintaining a low Ca2+ concentration in close
350
proximity to the TRPVs pores, and thereby ensuring the "downhill" movement of Ca2+ into
351
the cell. Although these proteins appear to be primarily associated with Ca2+ transport, they
12
352
may also be involved in protecting the cells from high concentrations of Ca2+ or from
353
apoptotic cellular degradation (Christakos et al. 2003).
354
Unlike the mammalian intestine, uterus and placenta, which contain mainly calbindin D9K,
355
the avian tissues contain almost only calbindin D28K. In the chick intestine and ESG, the
356
protein is localized primarily in the absorptive cells and in the tubular gland cells,
357
respectively (Lippiello et al. 1975; Jande et al. 1981; Wasserman et al. 1991). Renal calbindin
358
D28K is exclusively localized in the distal convoluted and collecting tubules (reviewed by
359
(Raval-Pandya et al. 1999; Christakos et al. 2005). In the chicken and quail intestine,
360
calbindin concentrations are higher in the proximal than in the distal segments (Taylor et al.
361
1967; Bar et al. 1976b). In all three major-Ca2+-transporting organs, calbindin content is
362
closely correlated with Ca2+ transport (Taylor et al. 1969; Morrissey et al. 1971; Bar et al.
363
1975a; Bar et al. 1979a; Bar et al. 1984b). However, whereas the calbindin contents in the
364
kidney and in the ESG are correlated with the mass of calcium transported (weight unit), the
365
intestinal calbindin is correlated with calcium transport capability (percentage absorption,
366
Fig. 1) rather than with the mass of calcium absorbed (Fig. 2) (Bar et al. 1979a; Bar et al.
367
1979b; Bar et al. 1984b; Bar et al. 1992b)).
368
Avian intestinal, ESG and kidney calbindins are identical (Taylor et al. 1972; Bar et al.
369
1976a; Fullmer et al. 1976), comprise 261 amino acids (Wilson et al. 1985; Hunziker 1986;
370
Fullmer et al. 1987) and contain six EF hands, four of which bind Ca2+ strongly. The apparent
371
Ka is 108M-1 to 106M-1. Lower affinity was observed for other cations, diminishing in the
372
order Ca2+> Cd2+> Sr2+> Mn2+> Zn2+> Ba2+> Co2+> Mg2+ (Ingersoll et al. 1971). The
373
calbindin D28K gene is about 19 kb long, consists of 11 exons (Minghetti et al. 1988; Wilson
374
et al. 1988) and is highly conserved in evolution. A putative vitamin D-responsive element
375
(VDRE) was identified on the mouse calbindin D28K promoter. Some observations also
376
indicate the presence of putative low active or inactive VDRE on the chicken gene encoding
377
calbindin D28K (reviewed in (Christakos et al. 1997; DeLuca 2004; Christakos et al. 2005)). In
378
addition an estrogen-responsive element was also identified on the 5'-flanking region of the
379
calbindin D28K promoter (Gill et al. 1995; Criddle et al. 1997).
380
381
13
382
383
384
385
386
387
388
389
Fig. 1. (upper panel) Relationship between duodenal calbindin and intestinal capability to absorb calcium
in non-laying  and laying hens during periods of shell calcification  (from (Bar et al. 1979a)). CaBP,
calbindin, Ca, total calcium); and (lower panel) Relationship between eggshell gland (EGS) calbindin and
shell calcium of laying hens during periods of shell calcification (with permission from (Bar et al.
1984b)).
14
390
391
392
Fig. 2. Plasma calcium, intestinal and plasma calbindin, and intestinal calcium absorption as functions of
calcium intake (with permission from (Bar et al. 1979b)).
393
394
At least in the avian intestine, kidney, ESG and brain, three species of mRNAs are
395
encoded. A major one (approximately 2.0 kb) and two minor species (approximately 2.7 and
396
3.0 kb, (Fig. 3) all encode calbindin D28K. However, despite their similarity, the synthesis of
397
avian calbindin is regulated differently (Table 3) in each of the three major transporting
398
organs (for details and references see (Bar 2008) and Bar, 2009, submitted).
399
Intestinal calbindin mRNAs and calbindin synthesis reflect the changes in 1,25(OH)2D3 in
400
the intestinal cell, whether these changes result from exogenous supplementation of vitamin
401
D derivatives (Wasserman et al. 1966; Bar et al. 1975b; Bar et al. 1976b; Bar et al. 1978b;
402
Bar et al. 1990b; Striem et al. 1991; Bar et al. 1992a) or occur in response to restrictions of
403
dietary Ca2+ and/or P (Wasserman et al. 1968; Morrissey et al. 1971; Bar et al. 1972b; Bar et
404
al. 1973a; Friedlander et al. 1977; Montecuccoli et al. 1977a; Bar et al. 1984a; Bar et al.
405
1990a), growth, age (Bar et al. 1981a; Bar et al. 1988; Bar et al. 1999; Bar et al. 2003),
406
maturation, or onset or arrest of laying (Wasserman et al. 1968; Bar et al. 1972a; Striem et al.
407
1991; Bar et al. 1992a; Nys et al. 1992a; Sugiyama et al. 2007).
15
408
409
410
411
412
413
414
415
416
417
418
419
420
421
422
423
Fig. 3. Visualization of calbindin mRNAs from the duodenum and eggshell gland (ESG) by Northern
blotting. (a) Effect of laying on duodenal calbindin mRNAs: Lane 1, vitamin-D-deficient chick; lane 2,
mature non-laying; lane 3, laying hen (from (Bar et al. 1992a)). (b) Effect of laying on ESG calbindin
mRNAs: Lane 1, laying hen duodenum; lane 2, ESG of mature non-laying; lane 3, ESG of laying hen
during period of ESG inactivity; lane 4, ESG of laying hen during period of shell calcification (from
(Bar et al. 1992a)). (c) Effect of shell calcification blocking of ESG calbindin mRNAs: Lane 1,
untreated laying hen; lane 2, laying hen treated with a single oral dose of the carbonic anhydrase
inhibitor acetazolamide; lane 3, laying hen following forced immature oviposition (from (Bar et al.
1998)). (d) Effect of shell quality: Lane 2, laying hen with shell-less eggs; lane 3, laying hen with
normal eggs; lane 4, laying hen with broken or cracked eggs; above are shown the previous last eggs,
Hens were sampled 17 h post oviposition (from (Bar et al. 1998). Membranes were hybridized with
oligonucleotide complementary to the mRNA sequence encoding amino acids 58-68 of chicken
calbindin (with permission). Similar results were obtained using the quantitative
hybridization assay".
“solution
16
424
425
426
427
428
429
430
431
432
433
434
435
436
437
438
439
Table 3. Differential regulation of avian calbindin: Effects of selected physiological and
nutritional alterations
___________________________________________________________________________
440
441
442
443
444
445
446
447
448
449
450
451
452
453
454
455
456
457
458
459
460
461
462
463
464
465
466
467
468
469
470
471
472
Cause/tissue
Intestine
Kidney
ESG
References1
___________________________________________________________________________
Vitamin D derivatives in vitamin-D-deficient2
+++3
++
=/+4
(Wasserman et al. 1966;
Corradino et al. 1968;
Taylor et al. 1972; Striem
et al. 1991)
1-hydroxylated derivatives in vitamin-D-fed
+++
=
=
(Bar et al. 1973c; Bar et
al. 1975b; Bar et al.
1976b)
Dietary Ca2+ restriction in vitamin-D-fed
+++
=/-
=/-
(Wasserman et al. 1968;
Bar et al. 1972a; Bar et al.
1973b; Bar et al. 1975b;
Bar et al. 1978b)
Dietary P restriction in vitamin-D-fed
+++
+++
=
(Morrissey et al. 1971;
Bar et al. 1973c; Bar et al.
1975b; Bar et al. 1984a)
=
=
ND5
(Bar et al. 1973c; Bar et
al. 1975b)
+++
+++
ND
(Bar et al. 1973c; Bar et
al. 1975b)
-
+
ND
(Bar et al. 1990a)
Growth
++
=
ND
(Bar et al. 1981a)
Maturation or gonadal hormones
++
=
=/+
(Bar et al. 1972a; Bar et
al. 1973b; Montecuccoli et
al. 1977b; Bar et al.
1978b; Bar et al. 1979a;
Navickis et al. 1979a;
Navickis et al. 1979b)
Laying
+++
=
+++
(Corradino et al. 1968;
Wasserman et al. 1968;
Bar et al. 1972a; Bar et al.
1973b; Bar et al. 1978b)
Shell calcification (on protein synthesis)
=
ND
=
Shell calcification (on mRNA synthesis)
=
ND
+++
Dietary Ca2+ restriction in 1-hydroxylated-D-fed
Dietary P restriction in 1-hydroxylated-D-fed
High dietary Ca2+ in D-fed
(Bar et al. 1975a)
(Nys et al. 1989; Striem et
al. 1991; Bar et al. 1992a;
Nys et al. 1992a)
__________________________________________________________________________
1
The table tries to bring together most earlier published quantitative or semi-quantitative comparisons, as well
as supporting evidence published later by other research teams. Many, but not all, other studies are mentioned in
the text and in the References list. Few of the very early studies used the chelex assay, but were confirmed later
with immunoassays or Western analysis.
2
Not laying.
3
The regulative response varied between non (=) to very strong (+++) or negative (-); ND, not detected;
4
Varied in accordance with laying rate.
5
Not determined.
17
473
As in the intestine, the full modulation of renal calbindin mRNAs requires vitamin D.
474
However, unlike intestinal calbindin, renal calbindin did not completely disappear in vitamin
475
D-deficient birds, and even retained part of its capability to be modulated in response to
476
dietary alteration (Bar et al. 1975b; Bar et al. 1990a). Restriction of dietary P, but not of
477
dietary calcium, as well as high dietary calcium, induced also the synthesis of renal calbindin
478
D28K but not of ESG calbindin D28K in birds (Bar et al. 1975b; Bar et al. 1984a; Rosenberg et
479
al. 1986; Bar et al. 1990a). Whereas none of the observed changes in intestinal calbindin and
480
its mRNAs could be attributed to changes in plasma Ca2+ content, renal calbindin mRNA and
481
calbindin were positively related to plasma Ca2+ (Taylor et al. 1972; Rosenberg et al. 1986;
482
Bar et al. 1990a) and to urinary Ca2+ excretion, independently of vitamin D status (Bar et al.
483
1975b; Rosenberg et al. 1986; Clemens et al. 1989; Bar et al. 1990a). The above findings do
484
not support the hypothesis that renal calbindin is involved in Ca2+ reabsorption, especially in
485
light of the fact that it is induced when the body is loaded with calcium (in P-restricted birds
486
or in those fed high-calcium diets).
487
Most of the available evidence does not support the idea that ESG calbindin D28k is
488
vitamin D dependent: endogenous or exogenous 1,25(OH)2D3 (Bar et al. 1976b; Bar et al.
489
1988; Bar et al. 1990b), as well as dietary alterations (Bar et al. 1973b; Bar et al. 1978b; Bar
490
et al. 1984a; Bar et al. 1984b; Bar et al. 1999; Ieda et al. 1999), had no effect on ESG
491
calbindin, whereas they did affect intestinal or renal calbindin; furthermore, ESG calbindin
492
mRNAs are induced in the shell-forming, vitamin D-deficient quail (Striem et al. 1991).
493
In the female bird, intestinal calbindin mRNA (Striem et al. 1991; Bar et al. 1992a) and
494
calbindin (Bar et al. 1972a; Montecuccoli et al. 1977b; Bar et al. 1978a; Bar et al. 1981b; Bar
495
et al. 1992a; Nys et al. 1992a; Wu et al. 1994; Bar et al. 1996) are moderately increased
496
during sexual maturation. Treatment with estrogen and testosterone in combination may
497
mimic this effect (Bar et al. 1979a; Navickis et al. 1979a; Nys et al. 1984c). However, the
498
ESG remains in a refractory state prior to actual reproduction, and calbindin mRNAs and
499
calbindin begin to appear during calcification of the first eggshell (Bar et al. 1973b; Bar et al.
500
1978a; Bar et al. 1978b; Striem et al. 1991; Bar et al. 1992a). In the ESG, but not the
501
intestine, calbindin mRNAs oscillate during the diurnal egg cycle, between near-zero and
502
high concentrations, in close temporal association with eggshell calcification (Figs.3, 4, 5)
503
(Nys et al. 1989; Striem et al. 1991; Bar et al. 1992a; Bar et al. 1992b; Nys et al. 1992b; Ieda
504
et al. 1995)).
505
18
506
507
508
509
510
Fig. 4. The circadian changes in duodenal and eggshell gland calbindin-mRNA and calbindin. ,
calbindin; , mRNA; , shell calcium (Ca). Mean ± SE. Means designated by different letter are
significantly different (P < 0.05) (with permission from (Bar et al. 1992a)).
19
511
512
a
c
b
513
514
515
516
517
518
d
519
520
521
522
523
524
525
526
527
528
529
530
531
532
533
534
535
Fig 5. The formation and degradation of calbindin and calbindin mRNA in the duodenum and the
eggshell gland (ESG) of the laying hen. (a) Degradation during an induced arrest of egg production or (b)
log of calbindin concentrations during an induced arrest of egg production. , duodenum; , ESG. (c)
Onset of egg formation. Triangulars, calbindin; circles, mRNA; (closed or open symbols are trials 1 & 2,
respectively). (d) Model simulation of the synthesis of ESG calbindin mRNA and calbindin at the onset of
production. A simulation algorithm was used; the estimated parameters adequately account for the
apparent lack of an observed variation in ESG calbindin during the laying cycle in spite of the wide
oscillations in the mRNA, as well as the changes in calbindin at the onset of laying. The half-times of
calbindin mRNA in the duodenum and shell gland were estimated at 2 and 3.6 h, respectively, and those
of calbindin at 13.9 and 32.6 h, respectively. The formation rates of calbindin mRNA were 0.37 and 0.17
pmol.h-1.g-1 and the rate of calbindin formation was 0.099 and 0.031 g.pmol.mRNA-1.h-1 in the duodenum
and shell gland, respectively. (with permission from (Bar et al. 1992a)).
536
537
Onset of laying markedly increased intestinal and ESG calbindin mRNA (Nys et al. 1989;
538
Bar et al. 1990b; Striem et al. 1991; Bar et al. 1992a; Nys et al. 1992a) and calbindin
539
(Wasserman et al. 1968; Bar et al. 1973b; Bar et al. 1976a; Bar et al. 1978a; Bar et al. 1978b;
540
Bar et al. 1992a; Sugiyama et al. 2007) synthesis in the intestine and the ESG. Early onset of
541
production is associated with a higher duodenal calbindin concentration than in late layers,
542
most likely as a result of a more severe physiological Ca+2 deficiency (Bar et al. 1972a; Bar et
543
al. 1973b; Bar et al. 1998).
544
Molting (Heryanto et al. 1997; Yosefi et al. 2003) and any other factor that arrests egg
545
production (Bar et al. 1973b; Bar et al. 1973a; Bar et al. 1992a) markedly reduce the intestinal
20
546
and ESG calbindin contents. Following molt, intestinal calbindin content was similar to or
547
even slightly lower than that prior to molt induction (Yosefi et al. 2003).
548
Similarly to duodenal-calbindin, ESG-calbindin is lower in non-laying hens or in hens
549
laying shell-less eggs than in those laying calcified eggs, and is lower in hens that form thin
550
eggshells than in those that form thick ones (Bar et al. 1984b; Nys et al. 1986b; Bar et al.
551
1988; Rabon et al. 1991; Bar et al. 1992a; Bar et al. 1992b; Kang et al. 1996; Bar et al. 1999;
552
Goto et al. 2002c).
553
In most studies estrogens (Navickis et al. 1979b; Nys et al. 1989; Striem et al. 1989; Bar
554
et al. 1990b; Striem 1990; Nys et al. 1992b; Corradino 1993; Corradino et al. 1993; Bar et al.
555
1996) only slightly induced calbindin D28K synthesis in the avian ESG (one to two orders of
556
magnitude smaller than that induced by shell calcification). Progesterone specifically
557
inhibited ESG calbindin synthesis (Bar et al. 1996; Goto et al. 2002b), an effect that was
558
markedly stronger than the observed effects of estrogens, which indicates that it was not due
559
its anti-estrogenic nature.
560
The accumulated evidences suggests that Ca2+ transport in the ESG, similarly to that in
561
the kidney, plays a major role in the synthesis of ESG calbindin mRNAs. It was hypothesized
562
that the regulative mechanism for the synthesis of calbindin mRNAs in the ESG is a complex,
563
multiple one, which involves, in addition to a major Ca2+-transport-related process, estrogen
564
and other endocrine factors (Nys et al. 1989; Striem et al. 1991; Bar et al. 1992a; Nys et al.
565
1992b; Corradino 1993; Corradino et al. 1993; Corradino et al. 1995; Bar et al. 1996; Bar et
566
al. 1999).
567
None of the reproductive factors–including maturation and onset of laying–that modulate
568
intestinal or ESG calbindin was found to affect renal calbindin synthesis in birds (Bar et al.
569
1978b).
570
2.3. Plasma membrane calcium-ATPase (Ca2+-ATPase or PMCA)
571
The PMCAs are a group of more than 30 isomers that use the energy stored in ATP to
572
extrude Ca2+ out of the cell against the electrochemical gradient (reviewed in (Davis et al.
573
1987; Wasserman et al. 1992; Bouillon et al. 2003; Stokes et al. 2003; Belkacemi et al. 2005;
574
Hoenderop et al. 2005b; Nijenhuis et al. 2005)). Briefly, the PMCA1b is the predominant
575
isomer expressed in the mammalian intestine, kidney and placenta (reviewed in (Howard et
576
al. 1993; Nijenhuis et al. 2005)) and the chicken intestine (Melancon et al. 1970; Strittmatter
577
1972; Davis et al. 1987) and kidney (Qin et al. 1993). In the intestine, kidney and placenta the
578
PMCAs are located on the basolateral membrane of the epithelial cell toward which Ca2+ is
579
transported (Borke et al. 1989a; Borke et al. 1989b; Borke et al. 1990).
21
580
The intestinal expression at the transcriptional level is modulated by vitamin D (reviewed
581
in (Zelinski et al. 1991; Wasserman et al. 1992) and also by a variety of factors that affect
582
vitamin D metabolism (Wasserman et al. 1992; Cai et al. 1993; Armbrecht et al. 1994; Zhu et
583
al. 1998). In addition a VDRE sequence was identified in the PMCA1 gene (Glendenning et
584
al. 2000). A few evidence support also the idea that estrogens also regulate PMCAs: (Dick et
585
al. 2003; Van Cromphaut et al. 2003; Van-Abel et al. 2003).
586
In laying birds PMCA(s) are found in the intestine and in the ESG. In the ESG they are
587
localized primarily in the apical-microvillar membrane facing the ESG lumen, rather than in
588
the basolateral membrane. The association of PMCA with Ca2+ transport, its dependency on
589
1,25-(OH)2D3 and estrogens were addressed previously in a recently published review (Bar
590
2008).
591
2.4. Sodium-calcium (Na+/Ca2+) exchange
592
The Na+/Ca2+ exchange mechanism (NCX) is a second transporting system involved in the
593
"uphill" extrusion of Ca+2 across the basolateral membrane of the epithelial cell, toward the
594
extracellular pool. At least three genes encode these transporter proteins in wide a variety of
595
mammalian cells (reviewed in (Belkacemi et al. 2005; Hoenderop et al. 2005b; Lambers et al.
596
2006a; Lytton 2007; van de Graaf et al. 2007; Perez et al. 2008)), but only NCX1 is widely
597
expressed in the calcium-transporting organs, i.e., the intestine, kidney and placenta. In
598
mammalian enterocytes, NCXs do not appear to play a major role in Ca2+ extrusion, whereas
599
the PMCA appear to be the main mechanism by which Ca2+ is extruded from the cells at the
600
basolateral surface. On the other hand, the kidney basolateral Ca2+ efflux is mainly mediated
601
by NCX1, and NCX1 appears to be regulated by Ca2+ (reviewed in (Lytton 2007)). The
602
calcium-regulating hormones, 1,25(OH)2D3 and PTH were found to regulate renal NCX1
603
mRNA synthesis and NCX1 activity, respectively. On the other hand, in an earlier study
604
(Ghijsen et al. 1983) rat intestinal NCX activity was not found to be affected by 1,25(OH)2D3.
605
NCXs were found also in the avian osteoblasts, in the chick embryo heart (Stains et al.
606
2002; Shepherd et al. 2007), and in the chick intestine, where it was induced in response to
607
calcium deficiency (Centeno et al. 2004). They have not yet been determined in the other
608
avian calcium-transporting organ, the ESG.
609
2.5. Carbonic anhydrase
610
The carbonic anhydrases (CAs) are a group of zinc-containing enzymes that catalyze the
611
reversible hydration of carbon dioxide. The CAs are involved in bone resorption and
612
calcification, ion transport, acid-base metabolism, and the movement of respiratory gases.
613
The CA family comprises three evolutionarily unrelated subfamilies without significant
614
sequence homology. At least 16 different isomers were identified in mammalian tissues
22
615
(reviewed in (Esbaugh et al. 2006; Purkerson et al. 2007)) and several novel isozymes have
616
also been identified in avian tissues (Holmes 1977). The commonest of these isomers in avian
617
tissues is CA-II (Holmes 1977). CAs were found in the avian kidney (Holmes 1977; Brown et
618
al. 1982; Gabrielli et al. 1998), epiphysis (Dulce et al. 1960)– specifically in bone osteoclasts
619
(Gay et al. 1974; Billecocq et al. 1990)– intestine (Nys et al. 1984b; Grunder et al. 1990;
620
Gabriella et al. 1994) and ESG (Benesch et al. 1944; Bernstein et al. 1968)– specifically in
621
the ESG epithelial cells (Arai et al. 1996). The CAs are present also in other cells, such as
622
gastric parietal cells and salivary glands, where their main role is to generate H+ and HCO3-
623
during acid-base regulation. The formation of HCO3- in the avian ESG appears to be of
624
especial importance for the deposition of CaCO3 in the shell, where it acts as the sole counter
625
ion for Ca2+. The dependency of CA on vitamin D is not yet clear: a VDRE region was
626
identified in the CA-II gene (Quelo et al. 1994), and 1,25(OH)2D3 was found to regulate the
627
transcription of CA-II in myelomonocytes (Lomri et al. 1992), and to induce their
628
differentiation ((Billecocq et al. 1990; Lomri et al. 1992). Vitamin D3 deficiency caused a
629
reversible reduction in CA activity in the ESG of the laying hen (Grunder et al. 1990), but CA
630
activity was found to be unrelated to plasma level, or to exogenous supplementation of
631
1,25(OH)2D3 (Nys et al. 1986b; Grunder et al. 1990).
632
Maturation and laying were associated with enhanced ESG CA-II activity (Pearson et al.
633
1977; Nys et al. 1986b; Kang et al. 1996), an association attributed mostly to estrogen
634
priming of the ESG (Holm et al. 2001). Molting inhibited CA activity in the ESG (Pearson et
635
al. 1977). Some (Ohashi et al. 1984; Kang et al. 1996), but not all (Grunder et al. 1976;
636
Salevsky et al. 1980; Balnave et al. 1992) publications have suggested that ESG-CA is higher
637
in hens that form thick eggshells than in those that form thin ones, but many of the factors
638
that cause shell thinning in wild birds are associated with reductions in ESG CA-II activity
639
(Lundholm 1997; Holm et al. 2006). The pattern of changes in ESG CA activity during the
640
egg cycle is also a subject of controversy (Salevsky et al. 1980; Kansal et al. 1984; Nys et al.
641
1986b; Balnave et al. 1992). Other factors known to affect ESG CA are the ambient
642
temperature and salinity in the drinking water (Kansal et al. 1984; Yoselewitz et al. 1989; Gill
643
et al. 1990; Balnave 1993; Khalafalla et al. 1998).
644
CA inhibitors, such as acetazolamide, rapidly (10 to 12 h after a single administration in
645
vivo) blocked shell calcification (Bernstein et al. 1968; Pearson et al. 1977; Eastin and
646
Spaziani. 1978b; Bar et al. 1992a; Bar et al. 1999) in spite of the availability of dietary
647
calcium and vitamin D3; they also reduced ESG and intestinal calbindin (Bar et al. 1992a; Bar
648
et al. 1999) and ESG Ca2+-ATPase (Lundholm 1990). Of interest is the finding that
649
acetazolamide in vitro reduced CA activity, but not Ca2+ transport (Ehrenspeck et al. 1971).
650
This is indicative of a possible indirect role of CA in Ca2+ transport. Thinning of the quail
23
651
eggshell caused by p-p'-DDT and DDE was associated with a reduction in ESG AC activity
652
(Bitman et al. 1970).
653
Lower concentrations of CA were found also in the intestinal mucosa of birds (Holmes
654
1977; Gabriella et al. 1994; Elbrond et al. 2004), but whereas the ESG CA activity was found
655
to be affected by the suppression of eggshell calcification, the intestinal activity remained
656
unchanged (Nys et al. 1984a; Nys et al. 1984b). The current models of intestinal Ca2+
657
transport (see 3.2) do not consider the involvement of CA, therefore, in more recent studies
658
only the changes in ESG CA, but not those in intestinal CA were determined. ((Grunder et al.
659
1990) and many others).
660
2.6. Osteopontin
661
Osteopontin (OPN) is a glycosylated, highly phosphorylated protein (reviewed in (Sodek
662
et al. 2000) and others), expressed in a variety of tissues that are characterized by Ca2+
663
transport, such as the bone (reviewed in (Butler 1989; Butler et al. 1996; Nakamura et al.
664
2003)), kidney (Rittling et al. 1999) and the ESG (Pines et al. 1995), and also in other cells
665
and tissues, including the immune system and tumors. OPN appears to have roles in wound
666
healing, inflammatory responses and bone remodeling, and it stimulates cellular signaling via
667
various receptors in many cells; these include bone cells, in which it appears to affect
668
migration and maturation of osteoclast precursors, attachment of osteoclasts to the mineral
669
phase of the bone, and osteoclast activity. OPN appears to be one of the major phosphorylated
670
proteins of the avian eggshell matrix (Mann et al. 2007); it is synthesized in and secreted from
671
the isthmus and the ESG of the laying bird (Pines et al. 1995; Lavelin et al. 1998; Lavelin et
672
al. 2000; Fernandez et al. 2003). Expression of ESG OPN, similarly to that of calbindin and
673
other ESG proteins, exhibited diurnal changes, and peaked during shell calcification (Pines et
674
al. 1995). However, whereas calbindin gene expression was stimulated by Ca2+ transport,
675
OPN expression was stimulated by the mechanical strain imposed by the forming egg
676
(Lavelin et al. 1998). No OPN gene expression was detected in the ESG of a pre-laying hen,
677
before the onset of reproduction, or after forced removal of the egg just before its entry into
678
the ESG. OPN was found to be synthesized by the epithelial cells of the ESG that line the
679
lumen. The synthesized OPN is immediately secreted out of cells and accumulates in the
680
eggshell. The presence of OPN in the organic matrix of the shell, especially in the mammillea
681
(mamillary cores (Fernandez et al. 2003; Chien et al. 2008b), the localization of the gene
682
encoding its formation specifically in the ESG cells, its circadian expression in the ESG, and
683
its occurrence in oviduct regions, coincided with the concomitant presence of the egg in each
684
region, and its involvement in calcification of the bone suggests that OPN may play a role in
685
shell calcification (Lavelin et al. 2000).
24
686
The definitive role of OPN in shell formation has not yet been established; expression of
687
its gene is stimulated by many growth factors and hormones, including 1,25(OH)2D3 (Prince
688
et al. 1987; Han et al. 2003). In addition, a DNA sequence responsible for binding VDR-RXR
689
heterodimer was identified on the OPN gene (Noda et al. 1990). However, and as noted above
690
with regard to calbindin, the presence of a VDRE on the gene promoter of CA does not
691
necessarily mean that the gene is induced in the ESG by 1,25(OH) 2D3. Although the
692
mechanism of shell biomineralization is poorly understood, the involvement of OPN in this
693
mechanism may be mediated via the fabrication of OPN-containing fibers (Fernandez et al.
694
2004; Chien et al. 2008,2009) in the collagen type X net of the outer shell membrane that is
695
formed in the isthmus. The mammilea, aggregates of organic material in which shell
696
crystallization is initiated, are then deposited in the isthmus. They consist of an OPN base and
697
a surface containing a calcium-binding keratan sulfate (mammillan). Ovoglycan (dermatan
698
sulfate, another matrix protein) may be also involved as modulator of the crystal growth. The
699
latter two proteins may be just as important as OPN in shell formation; however, the temporal
700
regulation of OPN hints at its possible involvement in the "on" signal for shell formation, as a
701
result of the mechanical strains imposed by egg-white formation in the magnum or by
702
"plumping" in the ESG.
703
3. Intestinal calcium absorption in the laying bird
704
3.1. Overall aspects and methodologies
705
3.1.1. Methodologies: Evaluation of intestinal Ca2+ absorption addresses either the capability
706
of the intestine to absorb Ca2+ (rate of absorption expressed as percentage of dietary or
707
medium content) or the mass of net or true absorption. Table 4 presents a few published
708
observations obtained in laying birds in vivo. These and other observations (Fig. 2; (Bar et al.
709
1979b)) indicate that the rate of absorption does not necessarily correspond to the actual mass
710
absorbed, as the latter depends on the dietary contents.
711
25
712
713
714
715
716
717
718
719
720
721
722
723
724
725
726
727
728
729
730
731
732
733
734
735
736
737
738
739
740
741
742
743
744
745
Table 4. Some factors affecting intestinal Ca2+ absorption in vivo1 in the laying fowl (Gallus
domesticus) and quail (Coturnix coturnix)
__________________________________________________________________________________________
Factor
Fowl
Quail
References2
2
3
Rate Mass
Rate Mass
__________________________________________________________________________________________
1-hydroxylated D3 metabolites in D fed birds3
+
+
+
ND4
(Bar et al. 1976b; Bar et
al. 1978b)
Low dietary Ca2+ 3
+
-
ND
ND
(Hurwitz et al. 1965;
Hurwitz et al. 1966a; Bar
et al. 1984a)
Low dietary P
+
+
ND
ND
(Bar et al. 1984a)
+
ND
ND
ND
(Nys et al. 1984c)
+
+
+
ND
(Hurwitz et al. 1965;
Hurwitz et al. 1967a;
Hurwitz et al. 1973a; Bar
et al. 1978a)
+
ND
ND
ND
(Nys et al. 1980),
+
+
+
ND
(Hurwitz et al. 1965; Bar
et al. 1976b)
=
ND
=
ND
(Wasserman et al. 1978;
Nys et al. 1980)
=/+
+
ND
ND
Gonadal hormones in immature female
chicken (in situ)
5
Laying
Laying (in situ) 5
Shell calcification (in vivo)
6
Shell calcification (in situ)5
Shell less (or thin shells) eggs3
(Hurwitz et al. 1967a;
Waddington et al. 1989)
__________________________________________________________________________________________
1
Measured either with the balance technique or with the non-absorbed reference substances (NARS).
2
Most earlier.
3
These finding were confirmed in situ (Nys et al. 1984c).
4
Not detected.
5
Measured with either tied or perfused intestinal loops.
6
This in vivo finding was confirmed by other groups of researchers who used either the NARS or other
methodologies (see 3.11 and 3.3.2 in text)
746
Earlier studies in mammals used a variety of methods, including: in vitro everted gut sacs
747
(Schachter et al. 1959; Harrison et al. 1960) or perfused loops, in situ-tied intestinal sacs
748
(Wasserman 1962; Wasserman et al. 1968; Wasserman et al. 1978) or Thiry Vella
749
(Nicolaysen 1943; Cramer et al. 1962) procedures. These procedures enabled evaluation of
750
the capability of the various intestinal segments to absorb Ca2+, or of the role of vitamin D in
751
this process, or elucidation of the mechanisms involved in Ca2+ absorption, rather than
752
estimation of net or true absorption. Determination of the latter requires the employment of
753
either the in vivo balance technique (Lengemann et al. 1957) or the use of non-absorbed
754
reference substances (NARS) (Marcus et al. 1962).
755
The few in vitro studies of birds yielded only little information. They addressed the
756
intestinal uptake (Sallis et al. 1962; Hurwitz et al. 1967b; Bar et al. 1969b; Bar et al. 1969a;
757
Holdsworth et al. 1975; Al Batshan et al. 1994; Wu et al. 1994) rather than the transfer of
758
Ca2+, because the chicken gut wall in vitro did not permit complete transfer of Ca2+ from the
26
759
mucosal to the serosal medium. Only ileal sacs of young chicks, which had been incubated in
760
a medium low in Na+ (Hurwitz et al. 1967b), exhibited mucosal to serosal transport (as
761
indicated by a serosal/mucosal ratio greater than 1) and a considerable effect of vitamin D.
762
However, in situ observations performed in the same study ((Hurwitz et al. 1967b) and in
763
others (see 3.1.2) identified the upper intestine as the main site of Ca2+ absorption in birds.
764
Much more information was obtained by means of in vitro everted upper (duodenum and
765
jejunum) intestinal sacs prepared from the chick embryo (Corradino 1973; Corradino et al.
766
1991). These in vitro studies confirmed the in vivo identification of the upper intestine as the
767
major absorption site, and thereby enabled focusing of subsequent studies on that region. In
768
addition, these studies provided valuable information on the vitamin D dependency of the
769
absorption process and on its regulation in birds, but not on its dependency on the nutritional
770
or physiological status.
771
In order to gain physiological information in situ-tied or -perfused intestinal loops were
772
used (Wasserman 1962; Hurwitz et al. 1967b; Morrissey et al. 1971; Bar et al. 1974; Nys et
773
al. 1980; Radwan et al. 1985; Annaka et al. 1989), alone or in combination with microscopic
774
imaging (Chandra et al. 1990; Fullmer et al. 1996). These in situ studies addressed the
775
vitamin D dependency of intestinal calcium absorption mechanisms, the site of absorption
776
and the effects of restrictions of dietary Ca2+ or P. The results obtained in these studies
777
enabled the in vitro findings to be extrapolated to the whole bird, but still addressed only the
778
capability to absorb Ca2+ rather the effects of various nutritional or physiological factors on
779
the actual absorption in vivo. Such factors include alteration of dietary composition and the
780
laying status.
781
In order to gain information on the true or net absorption (either capability or actual) as
782
well as on the effects of various nutritional or physiological factors, several in vivo
783
methodologies have been applied. Some studies employed constant feeding (Driggers et al.
784
1949) or single intubations (Clunies et al. 1993) of radioactive calcium into the proventricus
785
or crop of laying hens, in order to estimate calcium absorption and/or the dynamics of body-
786
calcium compartments, including the bone.
787
Some of the other in vivo methodologies that were applied in mammals, even if they
788
provided information on the true or net absorption (in mass units), were not necessarily
789
completely suitable for use with birds. The balance method, although it provides estimations
790
of the actual absorption in mammals, cannot differentiate between renal and intestinal
791
excretion of Ca2+ in birds, whose urine and feces are both excreted via a single exit, the
792
cloaca. Therefore, in birds, the balance technique estimates the retention of the mineral rather
793
than its net or true absorption. Colostomy, followed by a balance study (Hurwitz et al. 1961),
794
enables feces and urine to be separated, and thus enables the determination of the true or net
27
795
Ca2+ absorption. However, the surgical treatment severely affects animal wellbeing, and often
796
interferes with normal egg laying, therefore, this technique, too, appears not to be completely
797
suitable for studies of reproducing female birds. Furthermore, as the balance method requires
798
steady-state conditions and relatively long sampling periods, this combined method appears
799
to be not fully adequate for detection of the changes in absorption during a single egg cycle.
800
The NARS technique overcomes these technical weaknesses and enables estimation of the
801
true absorption from the apparent mineral/NARS ratios in the diet and in the lower ileum. In
802
laying birds this technique provides the best estimations of the true absorption of Ca2+ or P
803
(Hurwitz et al. 1965; Hurwitz et al. 1966b; Hurwitz et al. 1973a; Bar et al. 1976a; Bar et al.
804
1978a; Cohen et al. 1978; Bar et al. 1984a) and other nutrients (Bielorai et al. 1973; Hurwitz
805
et al. 1973b)) in vivo. Data obtained with this technique confirmed many of the earlier
806
findings obtained in vitro or in situ (see 3.1.2, 3.1.3 and 3.3,2).
807
3.1.2. Site of absorption: In both mammalian and avian species, the proximal intestine
808
appears to have greater capability than the distal intestine to absorb Ca2+ in vivo (Wasserman
809
1962; Lengemann 1963; Cramer 1965; Hurwitz et al. 1967b; Pansu et al. 1983; Clunies et al.
810
1993), and it exhibits the most pronounced effect of vitamin D on Ca2+ absorption in vivo.
811
These in vivo findings were supported by in vitro studies (Schachter et al. 1959; Harrison et
812
al. 1960; Corradino 1973; Pansu et al. 1983). In mammals, despite the lack of TRPVs in
813
the distal intestine, the ileum is considered to be the major site for dietary calcium absorption,
814
most likely via a paracellular route (see 2.1, 3.2), because of the longer transit half-time
815
(reviewed in (Bronner 2003; Wasserman 2004)), and the lack of TRPVs. In birds, most of the
816
calcium is absorbed before it reaches the lower ileum, most likely as a result of the high
817
efficiency of the proximal intestine in absorbing Ca2+, and of the lower ileal electrochemical
818
potential difference (ECPD) (see 3.2, 3.3) (Hurwitz et al. 1966b; Hurwitz et al. 1972; Hurwitz
819
et al. 1973a).
820
3.1.3. Intestinal absorption of Ca2+ in birds, as influenced by nutrition or physiological
821
status: Vitamin D and its metabolites were found to be the most important factors regulating
822
intestinal Ca2+ absorption, both in growing non-laying birds (Migicovsky et al. 1951;
823
Wasserman 1962; Hurwitz et al. 1967b; Hurwitz et al. 1972; Corradino 1973) and in laying
824
birds (Table 4, (Hurwitz et al. 1972; Bar et al. 1976a; Cohen et al. 1978). This fundamental
825
fact was observed by means of in vitro, in situ and in vivo methodologies. Dietary alteration
826
of vitamin D metabolism caused by dietary calcium or P restrictions modulated the intestinal
827
absorption of Ca2+ (Nicolaysen 1943; Migicovsky et al. 1951; Wasserman 1962; Hurwitz et
828
al. 1965; Wasserman et al. 1968; Morrissey et al. 1971; Bar et al. 1973c; Hurwitz et al.
829
1973a; Bar et al. 1984a). The effect of dietary P restriction appears not to be fully dependent
830
on 1-hydroxylation of vitamin D3 in the kidney (Bar et al. 1973c; Bar et al. 1975b). Increased
28
831
dietary calcium diminished absorption capability (percentage absorption) but increased the
832
mass of absorption (Bar et al. 1979b). Some evidence suggests that the chemical or physical
833
form of dietary calcium may influence its absorption or retention in the growing chick
834
(Guinotte et al. 1991) or the laying hen (Chandramoni et al. 1998; Scheideler 1998;
835
Lichovnikova 2007). Some other evidence suggests that, as in the rat (Armbrecht et al.
836
1980a), also in the not laying birds, age, breed, rate of growth and sexual maturation (Wu et
837
al. 1994) or treatment with gonadal hormones (Nys et al. 1984c) may affect calcium
838
absorption. Whereas the effect of age on mammalian intestinal Ca2+ transport was indicated
839
directly in many studies ((Nicolaysen et al. 1953; Hansard et al. 1957; Armbrecht et al.
840
1980b) and others), the effect of age or rate of growth in non-laying birds is less obvious and
841
was indicated mostly indirectly (Bar et al. 1981a; Fox et al. 1981; Hurwitz et al. 1996). On
842
the other hand, in vivo studies of the laying hen indicated that there are also age-dependent
843
changes in Ca2+ absorption; however, these changes mostly result from the changes in Ca2+
844
requirements associated with the changes in laying rate (Hurwitz et al. 1962; Scott et al.
845
1991). In addition, intestinal Ca2+ absorption is induced or diminished, respectively, by the
846
onset ((Hurwitz et al. 1973a; Bar et al. 1978a; Nys et al. 1980); reviewed in (Gilbert 1983)) or
847
arrest of egg laying (see 3.3.1). However, the intestinal capability to absorb Ca2+ did not reach
848
its maximum at the onset of production, but gradually increased during the early laying period
849
(Hurwitz et al. 1960; Scott et al. 1991).
850
3.2. Mechanisms of intestinal absorption
851
This issue was extensively reviewed in (Wasserman 1997; Bouillon et al. 2003; Bronner
852
2003; Wasserman 2004; Hoenderop et al. 2005b; Wasserman 2005; Perez et al. 2008; Khanal
853
et al 2008), among others. In birds, and mammals the relationship between luminal Ca2+
854
concentration and Ca2+ absorption suggests that the overall absorption reflects a sum of
855
saturated and unsaturated processes. Whereas the saturated process corresponds to active
856
transcellular transport, the unsaturated process involves diffusion through a paracellular route.
857
Briefly, the transcellular mechanism, at least in birds, acts predominantly at the proximal
858
intestinal segments, the duodenum and jejunum. It consists of three major steps: entry of Ca2+
859
through the brush border, facilitated diffusion or movement to the basal membrane, and
860
extrusion through the basal membrane. The first step proceeds down the chemical gradient of
861
Ca2+ that results from the low cellular concentration (10-7 M) and the high intestinal lumen
862
concentrations of Ca2+ from dietary sources (>10-3 M). This step appears to be facilitated by
863
TRPV6 (see 2.1.) and to a lesser extent by TRPV5.
864
The second step appears to be related to the presence of intestinal calbindins. Although
865
this relationship was elegantly visualized in 1990 by (Chandra et al. 1990) (see 3.1.1), it had
29
866
been suggested 24 years earlier (Wasserman et al. 1966) and was subsequently confirmed by
867
many other studies (Hurwitz et al. 1969b; Bar et al. 1972a; Freund et al. 1975). Kinetic
868
evidence supports the idea that intestinal calbindin facilitates Ca2+ absorption (Feher 1984;
869
Feher et al. 1992; Koster et al. 1995). In this regard, calbindin, may act as a transporter
870
protein (Feher 1984; Feher et al. 1992; Koster et al. 1995) or as a buffer that maintains the
871
chemical gradient of Ca2+ required for the undisturbed action of TRPVs (reviewed in
872
(Lambers et al. 2006b; Christakos et al. 2007; Schoeber et al. 2007). Some evidence also
873
indicates the occurrence of calbindin-mediated cytosolic-free diffusion of Ca2+ and of
874
vesicular transport of Ca2+ (reviewed in (Nemere et al. 1990; Norman et al. 2002; Larsson et
875
al. 2003; Dusso et al. 2005)). In addition to the hypothesized role of calbindins in Ca2+
876
transport, they may also be involved in protecting the cells from high concentrations of Ca2+
877
or from cellular degradation via apoptosis (Christakos et al. 2003). However, as the true or
878
net Ca2+ absorption in birds fed adequate P is positively related to its dietary intake, and is
879
negatively related to the intestinal rate of absorption or calbindin content (Fig. 2.) (Bar et al.
880
1979b), it appears that in the intestine calbindin acts as a transporter rather than as a buffer
881
protein. Otherwise, intestinal calbindin would be increased rather than decreased in birds fed
882
high dietary Ca2+. This hypothesis is somewhat weakened by the recent finding that
883
calbindin-D9K and TRPV6 are not required for vitamin D3-mediated Ca2+ absorption in the
884
mammalian small intestine (Akhter et al. 2007; Benn et al. 2008). These findings suggest that
885
1,25(OH)2D3 may affect intestinal absorption of Ca2+ via an alternative, the paracellular,
886
pathway.
887
The energy-dependent third step proceeds up the chemical gradient of Ca2+ that results
888
from the low cellular Ca2+ concentration (10-7 M) and the higher plasma Ca2+ concentration
889
(1.25 to 1.50 10-3 M). This step is facilitated by PMCA (see 2.3) and, to a lesser extent, by
890
NCXs (see 2.4). Components of all three steps of transcellular transport are vitamin D
891
dependent (see 2), because TRPV6 and TRPV5, calbindins and PMCA and, most likely,
892
Na+/Ca2+ exchanger genes all comprise a VDRE and/or are unaffected in the intestine of
893
VDR-knockout animals, and/or are stimulated in normal animals by 1,25(OH)2D3 or by
894
factors that affect its formation, such as dietary Ca2+, age, pregnancy, lactation, or egg laying.
895
The paracellular passive transport capability through the tight junctions occurs along
896
almost the whole length of the intestine, driven by the ECPD (Ussing 1949). As the electrical
897
potential difference (EPD) between blood plasma and the intestinal lumen is +5 to +15 mV
898
(blood always positive with respect to intestinal lumen), a chemical gradient is required in
899
order to maintain a positive ECPD between intestinal lumen and blood plasma. Such a
900
chemical gradient occurs in most animals that are fed adequate Ca2+ (Fig. 6). This suggests
30
901
that although the two mechanisms–paracellular and transcellular–appear to account for the
902
overall absorption, the paracellular transport is more important in animals fed adequate Ca2+.
903
904
905
906
907
908
Fig. 6. Relationship between the lumen-blood electrochemical potential difference (ECPD) of calcium,
and calcium absorption in the duodenum (closed symbols) and jejunum (opened symbols) of laying hens
fed diets containing 0.6 (circles), 1.8 (squares) and 4.0% calcium (triangulars). Calculated from data
given in (Hurwitz et al. 1969b)
909
910
The possible involvement of 1,25(OH)2D3 in paracellular transport through the tight
911
junctions (TJ) is a matter of controversy. The TJ connects between epithelial cells and forms
912
a biological barrier. Some evidence supports the idea that paracellular transport is induced by
913
vitamin D (reviewed in (Wasserman 1997; Wasserman 2004)) or its active derivatives (Bar et
914
al. 1978b; Cohen et al. 1978). This evidence indicated, among other phenomena, that in birds
915
vitamin D affected the bidirectional flux in vivo (Hurwitz et al. 1972), and that 1-
916
hydroxylated derivatives of vitamin D3 affected Ca2+ absorption only during the period of
917
shell calcification, in spite the lack of change in calbindin content (Bar et al. 1976b; Cohen et
918
al. 1978) (see also 3.3.2.1). Other related phenomena observed in mammals were reviewed in
919
(Wasserman 2005). Some other publications, dealing with non-laying animals ((Nellans et al.
920
1978; McCormick 2002) and others; reviewed in (Wasserman 2004)) oppose this hypothesis.
31
921
More recent studies supported the idea that the tight junction (TJ) proteins, permeability
922
and paracellular transport (reviewed in (Schneeberger et al. 2004; Van Itallie et al. 2006))
923
seem to be controllable. It appears that 1,25(OH)2D3 and VDR, as well as cellular Ca2+, are
924
among the factors responsible for preserving the integrity of TJ complexes, up-regulating TJ
925
proteins, and modulating TJ permeability and paracellular Ca2+ transport (Tang et al. 2003;
926
Kutuzova et al. 2004; Fujita et al. 2008; Kong et al. 2008). These findings further support the
927
hypothesis that 1,25(OH)2D3 may regulate paracellular Ca2+ transport also.
928
3.3. Absorption of Ca2+ in the laying bird
929
3.3.1. Development of absorption capability: The impressive intestinal Ca2+ absorption
930
capability of the laying bird is built up, in parallel with the increased demands for Ca2+ during
931
growth, maturation and onset of reproduction (Fig. 7, Table 4). Accelerated growth (Bar et al.
932
1981a; Hurwitz et al. 1995; Bar et al. 2003) increased the Ca2+ flux from blood to bone. The
933
growth rate, in turn, is controlled by genetic, nutritional, environmental and zootechnical
934
factors, and involves growth, thyroid and other hormones. Detection of homeostatic error
935
(i.e., change) (Hurwitz 1996; Ramasamy 2006; Bar 2008) in blood plasma Ca2+ level elicits
936
enhanced PTH secretion and, consequently, vitamin D metabolism, and acceleration of the
937
three presently known mechanisms associated with the active transcellular absorption of Ca2+.
938
Passive paracellular transport of Ca2+ is, most likely, also stimulated by vitamin D (see 3.2).
939
Later, following attainment of a certain minimal BW, light stimulation induces the synthesis
940
and activity of hypothalamic-pituitaric stimulating hormones and, consequently, the onset of
941
gonadal activity. As a result, estrogen/androgen-dependent new medullary bone and plasma
942
Ca2+ binding proteins (synthesized in the liver) are formed. All of these processes drain Ca2+
943
from the extra-cellular fluids and induce further vitamin D metabolism, either directly or
944
through PTH secretion. During this stage of maturation the gonadal activity stimulates the
945
development of the oviduct (including the ESG). Finally, the onset of laying of calcified eggs
946
imposes severe extra demands upon Ca2+ homeostasis, resulting in further induction of
947
vitamin-D-dependent intestinal Ca2+ absorption, especially during the period of shell
948
calcification. The intestinal capability to absorb Ca2+ does not reach its maximum at the onset
949
of laying, but continues to increase gradually during the early laying period (Hurwitz et al.
950
1960; Scott et al. 1991).
951
32
952
953
954
955
956
957
958
959
960
961
962
963
964
965
966
Fig. 7. Development of the intestinal and eggshell gland (ESG) Ca 2+ transport capabilities in the laying
bird. First phase - growth, white rectangular and arrows; second phase - maturation, gray (no line around)
rectangular and arrows; third phase - laying, black rectangular and arrows. For details see text (2, 3.3.1).
Components of the transport mechanisms are printed in italic fonts. In parentheses are listed components
of intestinal paracellular transport not yet found to be directly dependent on vitamin D (dependency is
characterized either by the responsiveness to vitamin D metabolites, the specific appearance in vitamin D
receptor-knockout animals or, in the case of proteins, also by the presence of a vitamin D-responsive
element on their encoding gene), but may be dependent on ESG CA. Ca, calcium; CAs, carbonic
anhydrases; ECPD, electrochemical potential difference; EPD, electrical potential difference; NCXs,
Na+/Ca2+ exchangers; PMCAs, Ca2+ATPases; OPN, osteopontin; TJ, tight junction proteins; TRPVs,
epithelial calcium channels. A single question mark indicates that the presence or involvement of this
component of transport was not yet determined in birds, whereas a pair of question marks indicates that
most of the available evidence does not support the idea that vitamin D regulates ESG Ca 2+ transport,
although such an idea cannot be completely rejected.
33
967
3.3.2. Circadian calcium absorption: The most remarkable finding concerning Ca2+
968
absorption in the laying bird is that it is noticeably more intense during the period of shell
969
calcification than during periods of ESG inactivity (Table 4; and (Hurwitz et al. 1965;
970
Hurwitz et al. 1966b; Hurwitz et al. 1973a; Bar et al. 1976a; Bar et al. 1978a; Cohen et al.
971
1978; Bar et al. 1984a)). Whereas the other nutritional and physiological responses were
972
observed in situ and in vivo, the effect of shell calcification was observed only by means of
973
the NARS techniques (see 3.1.1), with the aid of
974
dioxide, but not polyethylene glycol ((Hurwitz et al. 1965; Bar et al. 1979b; Sunahra et al.
975
1989; Waddington et al. 1989) and unpublished results). However, this finding was supported
976
by the kinetic study of (Clunies et al. 1993) and by the study of (Watanabe et al. 1992) on the
977
venous: arterial (duodenal: carotis) ratios of phosphorus, total calcium and Ca2+ , as well as by
978
the higher daily net absorption of Ca2+, observed by the balance technique, on laying days than in
979
non-laying days (Taylor and Kirkley, 1967). On the other hand, the effect of shell formation on
980
Ca2+ absorption capability was not confirmed by application of the in situ loops methods
981
(Wasserman et al. 1978; Nys et al. 1980). This discrepancy could have arisen because the
982
medium composition in the in situ studies did not reflect the lumen content in vivo, especially
983
with regard to the activity or solubility of Ca2+ (Hurwitz et al. 1969b) and their variations
984
during the egg cycle (Nys et al. 1980) (see 3.3.2.2 and 3.3.2.3).
91
Y,
144
Ce, chromic oxide or titanium
985
Whereas the combined transcellular and paracellular transport during the period of shell
986
formation account for net absorption of about 80 and 65% of the dietary Ca2+ intake in hens
987
and quail, respectively, much less (36 and 18%, respectively) is absorbed during the period of
988
ESG inactivity. Non-laying hens and quail absorbed slightly less (23 and 17%, respectively)
989
(Hurwitz et al. 1969a; Hurwitz et al. 1973a; Bar et al. 1976a; Bar et al. 1976b).
990
The increased calcium absorption during shell formation corresponds to the decreases in
991
plasma Ca2+ and the increased plasma PTH (Dacke 1976; van de Velde et al. 1984; Singh et
992
al. 1986), the increased intestinal content of soluble calcium (Mongin 1976b; Mongin 1976a),
993
acidosis (Mongin et al. 1964; Cohen et al. 1974; Wideman et al. 1985) and the changes in
994
plasma content of the reproductive hormones during the ovulatory cycle (reviewed in (Etches
995
1996)).
996
3.3.2.1. The vitamin D dependency: The mechanism of the circadian variation in Ca2+
997
absorption in the laying domestic bird is not yet clear. As mentioned above, it appears to be
998
sensitive to vitamin D; in vitamin-D-fed birds, an exogenous supply of 1-hydroxylated
999
derivatives of vitamin D markedly affected Ca2+ and P absorption during shell formation,
1000
whereas its effect during the period of ESG inactivity (when shell was not being formed) was
1001
small or negligible (Bar et al. 1976b; Cohen et al. 1978). The fact that shell formation affects
34
1002
Ca2+ absorption in birds fed vitamin D3, as well as in those fed 1OHD3 suggests that the
1003
increased absorption is not dependent on 1-hydroxylation in the kidney. This idea is
1004
supported by our earlier findings on the lack of considerable enhancement of renal 1-
1005
hydroxylase activity or on the plasma content of 1,25(OH)2D3 (Table 2b; reviewed in (Bar
1006
2008), and it was even suggested that 1,25(OH)2D3 production decreased during shell
1007
calcification (Kenny 1976)). Some findings did indicate diurnal changes in vitamin D
1008
metabolism (reviewed in (Bar 2008)), but as the build-up of genomic effects of 1,25(OH)2D3
1009
(metabolism, transcription and translation; (Lawson 1978; Bar et al. 1992a)) requires several
1010
hours, the circadian changes in calcium absorption during the relatively short egg cycle could
1011
not be attributed to any circadian change in vitamin D metabolism. Nevertheless, the increase
1012
in absorption during shell formation could not be mediated through calbindin, which
1013
remained almost unchanged during the laying cycle (Bar et al. 1972a; Bar et al. 1975a; Bar et
1014
al. 1976a; Cohen et al. 1978; Wasserman et al. 1978; Nys et al. 1992a; Ieda et al. 1995; Goto
1015
et al. 2002a). As the available data also do not indicate the occurrence of circadian changes in
1016
the other components of the transcellular mechanism, the hypothesis that, during shell
1017
formation in vitamin-D-fed birds, vitamin D interferes with the paracellular, rather than with
1018
the transcellular transport, is further supported.
1019
The enhanced plasma PTH concentration during shell formation (Table 2b) does not
1020
appear to be associated with an immediate vitamin D-dependent effect on Ca2+ absorption,
1021
because of the time required for vitamin D metabolism to be expressed (Lawson 1978; Bar et
1022
al. 1992). In addition, temporarily high levels of circulating PTH have not been found to
1023
affect temporary intestinal Ca2+ absorption, with the exception of a very few cases (reviewed
1024
in (Nemere et al. 2002)).
1025
3.3.2.2. Acidosis: Mammalian nutritional acidosis, but not environmental acidosis, was
1026
widely studied and the findings on its effects on intestinal calcium absorption were
1027
inconsistent, and have aroused controversy (Gafter et al. 1980; Goulding et al. 1984; Favus et
1028
al. 1986). Recently (Charoenphandhu et al. 2006), who used the rat as a model animal,
1029
suggested that chronic metabolic acidosis acts on TJ proteins and stimulates the paracellular
1030
transport. In addition, it stimulates the expression of TRPV6 and PMBA1b, which are known
1031
to be involved in active intestinal transcellular transport of calcium (see 3.2).
1032
The direct effect of acidosis on calcium absorption in laying birds was not determined. In
1033
the laying chicken, which calcifies shell mainly during the dark period of the day, acidosis
1034
occurs in close temporal association with the changes in calcium absorption and shell
1035
calcification that take place during the shell cycle. This indicates a possible involvement of
1036
acidosis in the cyclic changes in calcium absorption capability, through its effect on intestinal
35
1037
solubility of Ca2+ (Mongin 1976b; Mongin 1976a). This hypothesis is somewhat weakened by
1038
the finding that in laying quail, which calcified shells mostly during the light period, acidosis
1039
reached a peak much earlier than maximal shell calcification (Dacke et al. 1973) and maximal
1040
calcium absorption.
1041
3.3.2.3. Electrochemical potential difference (ECPD): In chicken and quail, both laying and
1042
non-laying, that are fed adequate Ca2+ a high positive ECPDs between the intestinal lumen
1043
and the blood were established in the duodenum, jejunum and proximal ileum, but not the
1044
distal ileum (Hurwitz et al. 1968; Hurwitz et al. 1969b). Thus, these birds appear to utilize the
1045
paracellular as well as the transcellular transport pathways. The lower ECPD in the distal
1046
intestinal segments of the chicken prevents absorption of significant quantities of Ca2+ in the
1047
distal ileum, and ensures that in chicken and quail, unlike mammals, Ca2+ is almost entirely
1048
absorbed before it reaches the distal ileum (Hurwitz et al. 1965; Hurwitz et al. 1972; Hurwitz
1049
et al. 1973a; Bar et al. 1976a). When the normal diets of the domestic birds contain more than
1050
0.6% Ca2+ the ECPD is maintained high enough to drive Ca2+ transport from blood to the
1051
intestinal lumen, and the paracellular route of transport appears to predominate. This
1052
hypothesis is supported by the finding that the vitamin-D-induced component of the
1053
transcellular pathway is down-regulated when dietary Ca2+ is increased (see 2, 3.2), which
1054
indicates that the transcellular pathway therefore contributes little to the overall absorption.
1055
The small change in plasma Ca2+, that is associated with shell calcification, together with
1056
the three- to fourfold increase in intestinal soluble calcium concentration (Mongin 1976b;
1057
Mongin 1976a) during shell formation is enough to affect the ECPD markedly and,
1058
consequently, to increase the passive Ca2+ absorption noticeably. Such increased absorption
1059
could also be promoted by any other change in intestinal lumen Ca2+ concentration that may
1060
result from dietary P deficiency, high dietary calcium intake, or low water intake; it also
1061
could be affected by changes in intestinal pH or by the diminution in the intestinal content
1062
during darkness. All of these factors combine to affect the intestinal calcium to P
1063
interrelationships. Recalculation of the data given in (Hurwitz et al. 1971) suggests that,
1064
whereas the total calcium to P ratio remains quite constant (ranging from 1.52 to 1.69) along
1065
the intestine, the ultrafilterable-calcium:P ratio increased from 1.73 in the duodenum to 12.1
1066
in the lower ileum. This suggests that absorption of P is faster than that of Ca2+, so that
1067
relatively more Ca2+ is left in the intestinal lumen, where it affects ECPD and paracellular
1068
transport.
1069
The involvement of vitamin D in the regulation of paracellular transport of Ca2+ is a matter
1070
of controversy. Our studies with the laying hen support the hypothesis that 1,25(OH)2D3 also
1071
affects paracellular transport: the specific, but notable, effect of 1-hydroxylated vitamin D
1072
metabolites on the absorption of Ca2+ through the paracellular route in the laying bird occurs
36
1073
exclusively during eggshell formation, although the calbindin (Bar et al. 1978b; Cohen et al.
1074
1978) and, most likely, the PMCA (see 2.3) concentrations remained unchanged during the
1075
egg cycle. Only when dietary calcium was lower than 0.6% and the ECPD became negative
1076
or too low, 1,25(OH)2D3 synthesis was up-regulated and the transcellular transport appeared
1077
to become the main mechanism.
1078
3.3.3. Bone–the other source of shell calcium: The increased absorption during shell
1079
calcification is not sufficient to satisfy the high Ca2+ requirement for shell calcification. In
1080
light of the passage times (50% output) of the ingested food through the esophagus (3 h),
1081
stomach (1 h), and the whole intestine (3 to 4 h) (Hurwitz et al. 1966b), and of the fact that
1082
most of the Ca2+ is absorbed in the upper intestine (Hurwitz et al. 1965; Hurwitz et al. 1973a;
1083
Bar et al. 1976a) during the first 75 to 78 min following its leaving the stomach, it is evident
1084
that, 6 to 10 h after the interruption of feeding, the intestine of the laying bird is almost empty
1085
of Ca2+. As eating stops with the onset of darkness, and as shell calcification in the domestic
1086
hen occurs mostly during the dark period (Tables 1), a considerable proportion of the shell
1087
Ca2+ must be derived from bone Ca2+ reserves. A conservative, careful estimate of this
1088
proportion is 20 to 40% of the eggshell Ca2+ (Comar et al. 1949; Driggers et al. 1949; Clunies
1089
et al. 1993). The bone reservoir is subsequently replenished with Ca2+ from the intestinal
1090
source during the periods of ESG inactivity and "plumping". Thus, in the high-producing
1091
domestic birds most of the shell Ca2+ of each individual egg is derived daily from the
1092
intestine. The resulting calcium balance [intake - (urine + shell + feces)] in the domestic hen
1093
varied between +80 and -121 mg/d (Hurwitz et al. 1960; Hurwitz et al. 1969a; Waddington et
1094
al. 1989; Clunies et al. 1993). Considering the fact that balance studies usually continue over
1095
3 to 7 d and that shell is not formed during some of these days (depending on the rate of
1096
laying), the balance may be even smaller on the days when shell is formed. Therefore, the
1097
calcium content in successive eggs in the clutch tends to decline progressively, especially in
1098
hens with long clutches, in old ones, or in those characterized by thin shells (Bar et al. 1988;
1099
Bar et al. 1999). The quail appears to be better adapted than the chicken with regard to shell
1100
calcification; it can obtain a higher proportion of shell Ca2+ from dietary source because it
1101
tends to oviposit at the end of the light period (reviewed in (Dacke 1979) and therefore
1102
calcifies eggs while the intestinal lumen contains enough Ca2+.
1103
37
1104
4. Eggshell transport of calcium
1105
4.1. Early studies on the evaluation of the capability and regulation of calcium transport
1106
in the eggshell gland
1107
Variables related to shell quality and shell mass have been widely employed for the
1108
estimation of ESG calcium transport in vivo. In fact such estimations reflect the accumulated
1109
contribution of all the mechanisms involved in shell formation (such as calcium homeostasis,
1110
acid/base balance, vitamin D metabolism, intestinal absorption, bone resorption and ESG
1111
activities), rather than the particular mechanism of ESG calcium transport. Furthermore,
1112
unlike the intestinal methodologies in vivo, the ESG ones were inadequate for the estimation
1113
of the ESG capability to transport Ca2+. More specific estimations were obtained during the
1114
7th and 8th decades of the 20th century (Ehrenspeck et al. 1967; Ehrenspeck et al. 1971;
1115
Pearson et al. 1973; Pearson et al. 1974; Pearson et al. 1977; Eastin et al. 1978b; Eastin et al.
1116
1978a). The most comprehensive studies were those performed by Eastin and Spaziani and by
1117
Pearson et al. Little was done since then (Nakada 1990; Vetter et al. 2005). Additional
1118
information on this issue was obtained from other reports that focused on the ESG fluid
1119
content (el Jack et al. 1967; Rieser et al. 1972; Edwards 1977; Arad et al. 1989; Nakada et al.
1120
1990; Nys et al. 1991; Panheleux et al. 1999), ESG electrical activity (Hurwitz et al. 1970;
1121
Cohen et al. 1973; Shimada et al. 1986), and on the activities and/or expression of proteins
1122
believed to be involved in shell formation (see 2, 4.2).
1123
The methodologies tried in seeking for the mechanisms and regulation of ESG Ca2+
1124
transport were: isolated ESG tissue in vitro (Ehrenspeck et al. 1971; Pearson et al. 1973;
1125
Laklia 1981; Vetter et al. 2005); use of Ussing (Ussing et al. 1951) type apparatus; ESG
1126
perfusion in situ (Eastin et al. 1978a; Eastin et al. 1978b); kinetic evaluation using radio-
1127
labeled calcium administered either as single doses or as continuously administration (Comar
1128
et al. 1949; Hurwitz 1964; Clunies et al. 1993); and determination of the venous:arterial
1129
(uterine:carotis) ratios of phosphorus, total calcium and Ca2+ contents (Watanabe et al. 1992).
1130
The major findings of these and other (Nakada 1990; Nakada et al. 1990) studies were: (a)
1131
more Ca2+ was transported in the ESG than in the other regions of the oviduct (Eastin et al.
1132
1978a; Laklia 1981); (b) non-laying or molting birds had a lower calcium transport (secretion
1133
from serosa or plasma to mucosa or lumen) and lower CA activity (Pearson et al. 1977; Eastin
1134
et al. 1978a) than laying birds; (c) Ca2+ secretion increased during the period of shell
1135
formation (Ehrenspeck et al. 1967; el Jack et al. 1967; Rieser et al. 1972; Nakada 1990;
1136
Watanabe et al. 1992; Clunies et al. 1993), and increased further if an egg or an egg-like
1137
insertion was present in the ESG (Edwards 1977; Eastin et al. 1978a; Nakada et al. 1990); (d)
1138
the EPD (plasma to lumen) was more positive in shell-forming hens (Hurwitz et al. 1970;
38
1139
Cohen et al. 1973); (e) The EPD favored the secretion of K+, Ca2+, and lumen-to-plasma
1140
transport of Cl-, but not the plasma-to-lumen flux of HCO3- or the lumen-to-plasma flux of
1141
Na+ (Pearson et al. 1974; Eastin et al. 1978b), except that at luminal Ca2+ contents of 6 to 8
1142
mM the ECPD would became negative (plasma-to-lumen) and then Ca2+ passive diffusion
1143
would be arrested; (f) however, Ca2+ secretion occurred even in the absence of EPD
1144
(Ehrenspeck et al. 1971; Pearson et al. 1973); (g) Ca2+ transport and CA activity appeared to
1145
be dependent on oxidative metabolism and on the active transport of Na+ (lumen to plasma)
1146
(Ehrenspeck et al. 1967; Ehrenspeck et al. 1971; Pearson et al. 1974; Vetter et al. 2005); (h)
1147
Ca2+ secretion was unaffected (Pearson et al. 1973), or continued, even if at a reduced level,
1148
when luminal Na+ was low or when its transport was prevented by the presence of ouabain
1149
(an Na+ transport inhibitor) (Pearson et al. 1974); (i) the CA inhibitor acetazolamide markedly
1150
affected CA activity (Eastin et al. 1978a; Lundholm 1990) and net Ca2+ transport in vitro, in
1151
situ (Pearson et al. 1974; Pearson et al. 1977; Eastin et al. 1978b; Laklia 1981) and in vivo
1152
(Bernstein et al. 1968; Sauveur et al. 1978; Bar et al. 1992a) (see also 2.5). On the other hand,
1153
(Ehrenspeck et al. 1971) found indications of increased permeability to Ca2+ in
1154
acetazolamide-treated ESG tissue in vitro; (j) the effect of acetazolamide was not observed in
1155
non-laying or molting hens (Pearson et al. 1977); (k) Ca2+ secretion was affected by luminal
1156
HCO3- but less affected by luminal Ca2+, whereas HCO3- movement depended mostly on its
1157
luminal concentration (Eastin et al. 1978b).
1158
4.2. Eggshell gland cyclic functionality
1159
The transport of Ca2+ and its complementary anion HCO3- by the ESG fluctuates during
1160
the egg-formation cycle, and both peak during the second half of the cycle. More specifically,
1161
the peak occurs during the later stage, beginning 11 to 12 h post ovulation and ending 22 to
1162
24 h post ovulation. Unlike its transport in the intestine, Ca2+ transport in the ESG is not
1163
associated with massive transport of many other nutrients, although it is associated with the
1164
secretion of HCO3- and the counter-transport of Na+, Cl- and H+ (Nys et al. 1999; Vetter et al.
1165
2005), and with the secretion of minute masses of shell matrix proteins. The development of
1166
the capabilities to transport Ca2+ and the other ions is associated with morphological and
1167
functional development of the oviduct, and is triggered by gonadal hormone activities,
1168
especially of estrogens (Oka et al. 1969; Navickis et al. 1979b; Hora et al. 1986; Bar et al.
1169
1990b; Striem 1990), during sexual maturation and onset of egg production. Estrogens appear
1170
also to maintain oviductal integrity and functionality through their anti-apoptotic capability
1171
(Monroe et al. 2002), as was clearly demonstrated during molt induction (Yoshimura et al.
1172
1997; Braw-Tal et al. 2004; Anish et al. 2008).
39
1173
In contrast to the situation in the intestine, Ca2+ homeostasis and vitamin D metabolism
1174
have no specific or major role (Navickis et al. 1979b; Striem et al. 1991; Corradino et al.
1175
1993) in the development of ESG capacity to transport Ca2+.
1176
1177
4.3. Shell-gland-specific proteins
1178
Many of the egg-membrane, shell-matrix and ESG proteins (reviewed in (Solomon 1991;
1179
Nys et al. 1999; Johnson 2000; Arias et al. 2001; Nys et al. 2001; Soledad Fernandez et al.
1180
2001)) are formed specifically in the ESG or are present there in high concentrations. Some
1181
of them (including collagen and many others) appear to be structural proteins, whereas others
1182
(including CA, calbindin, CaATPase, Na+-K+ATPase, parathyroid hormone-related peptide
1183
(PTHRP), VDR and other receptors) reveal specific functionality or appear to have both
1184
structural and functional characteristics (as with OPN or dermatan sulfate).
1185
Several of the ESG proteins, (such as calbindin (see 2.2), nVDR (Ieda et al. 1995),
1186
estrogen receptors (ER) (Kawashima et al. 1985), progesterone receptors (PR) (Kawashima et
1187
al. 1982), PTHRP (Thiede et al. 1991), glypican-4, 1-Na+-K+-ATPase (Lavelin et al. 2001;
1188
Lavelin et al. 2002) and OPN (Pines et al. 1995)) are transcribed in a circadian manner.
1189
Whereas calbindin, VDR and 1-Na+-K+-ATPase (in the glandular epithelium) are stimulated
1190
by Ca2+ transport (Bar et al. 1973b; Nys et al. 1989; Striem et al. 1991; Ieda et al. 1995;
1191
Lavelin et al. 2001; Goto et al. 2002c), a few others, e.g., OPN, 1-Na+-K+-ATPase (in the
1192
pseudostratified epithelium) and glypican-4 are stimulated by the mechanical strain imposed
1193
by the forming egg (Lavelin et al. 1998; Lavelin et al. 2001; Lavelin et al. 2002). The
1194
circadian transcription does not necessarily account for the circadian functionality. On the
1195
assumption that the differences between the kinetic rates of synthesis and of degradation of
1196
the fluctuating proteins and their mRNAs in the ESG are similar to those observed for
1197
calbindin, i.e., about one order of magnitude (Bar et al. 1992a), the fluctuations in the
1198
mRNAs would not be expected to cause significant fluctuations in the protein concentrations
1199
and, therefore, would not be relevant to the daily changes in functionalism–at least not during
1200
a single clutch of more than three eggs. However, prolongation of the intervals between
1201
successive eggs, i.e., at the ends of clutches, for more than 20 h may markedly reduce
1202
concentrations of these proteins as previously shown for calbindin (Montecuccoli et al.
1203
1977b).
1204
Eggshell calcification, which occurs in the ESG requires the interaction of many
1205
processes. These include: transcellular and/or paracellular transport of Ca 2+, the transfer of
1206
other ions and water during the early phase of egg presence in the ESG, when ovalbumin (egg
40
1207
white) swelling ("plumping") occurs, as well as during the later phase of shell calcification;
1208
egg movement along the oviduct, and oviposition driven by oviductal tissue contractions and
1209
their regulation; secretion of shell matrix proteins; and recognition by receptors of the many
1210
hormones involved in oviduct development and functionality. Whereas the receptors of the
1211
gonad hormones are found in higher concentrations in the ESG (Turner et al. 1978; Tanaka
1212
1980; Kawashima et al. 1982) than in the intestine (Agemori et al. 1984), the VDR content of
1213
the ESG appears to be markedly lower than that of the intestine (by a factor of three to seven)
1214
(Coty 1980; Bar et al. 1984b). Despite the lower VDR content of the ESG, this organ is
1215
characterized by relatively high concentrations of vitamin-D-dependent proteins, i.e., proteins
1216
encoded by genes known to have a VDRE, or vitamin-D-induced proteins, including: CA,
1217
calbindin, CaATPase (see 2), VDR itself, and OPN (Prince et al. 1987; Noda et al. 1990).
1218
However, unlike the well-documented vitamin D dependency of the intestinal absorption of
1219
Ca2+, the vitamin D dependency of ESG transport of Ca2+ is not certain. This uncertainty, in
1220
part, results from the difficulties of distinguishing between a possible specific effect of
1221
vitamin D on the shell calcification, on the one hand, and, on the other hand, an indirect effect
1222
induced by egg formation, since every factor that impairs or delays egg laying will
1223
consequently indirectly inhibit vitamin D metabolism and expression (reviewed in (Bar
1224
2008)), because of the decline in physiological Ca2+ demands. The apparent lack of an effect
1225
of vitamin D on ESG transport of Ca2+ is supported by the finding (Striem et al. 1991) that
1226
laying quail fed a vitamin-D-deficient, high-calcium diet exhibited all the symptoms typical
1227
of vitamin D-deficiency in the intestine, bone and blood, but continued to lay partially
1228
calcified eggs and to maintain for a long period moderate contents of the vitamin-D-
1229
dependent protein, calbindin and its mRNAs.
1230
4.4. Mechanism of calcium transport in the eggshell gland
1231
The available data appear to support the hypothesis that calcium secretion into the ESG
1232
lumen, similarly to the intestinal absorption process, occurs by both active transport and
1233
passive diffusion (Eastin et al. 1978a; Eastin et al. 1978b). Two of the three components
1234
involved in transcellular intestinal Ca2+ transport, i.e., calbindin and Ca2+ATPase, are found
1235
in the ESG and in the distal isthmus (Corradino et al. 1968; Eastin et al. 1978a; Eastin et al.
1236
1978b; Wasserman et al. 1991) tissues. Their presence in the distal isthmus suggests that
1237
there is active Ca2+ transport in this region, which is also known to secrete the mammillae
1238
where the early seeding of the eggshell Ca2+ crystals is initiated. In the ESG, calbindin is
1239
localized mainly in the tubular gland that is considered to be the major origin of eggshell Ca2+
1240
(Wasserman et al. 1991). The Ca2+ATPase is localized primarily in the apical-microvillar
1241
membranes of the same tubular gland cells (Yamamoto et al. 1985; Wasserman et al. 1991),
41
1242
facing the ESG lumen where shell calcification occurs. Thus, although the presence in the
1243
ESG of the third component of active/transcellular Ca2+ transport, TRPVs, has not yet been
1244
confirmed (see 2.1), it is most likely that TRPVs (also found in the mammalian uterus) are
1245
present there, and that transcellular transport is involved in eggshell calcification.
1246
Many studies (el Jack et al. 1967; Mongin et al. 1970; Rieser et al. 1972; Edwards 1977;
1247
Arad et al. 1989; Nakada et al. 1990; Nys et al. 1991; Panheleux et al. 1999) indicated an
1248
increase in ESG luminal content of Ca2+ during shell calcification. This suggests that there
1249
was an apparent "uphill" transport of Ca2+ and supports the hypothesis that a major portion of
1250
the secretion of Ca2+ into the ESG lumen occurs against the ECPD and involves active
1251
transport. However, the positive (plasma with respect to mucosa) electrical potential
1252
difference (EPD) (Hurwitz et al. 1970; Cohen et al. 1973; Pearson et al. 1973; Eastin et al.
1253
1978a) during shell calcification provides a sufficient electromotive force to ensure the
1254
transport of Ca2+ from blood to lumen against the chemical gradient, and to maintain a
1255
“steady state” calcium activity in the ESG that is over twice (Hurwitz et al. 1970) to four
1256
times (Eastin et al. 1978b) as high as that in the blood plasma. Furthermore, whereas the
1257
elevation in ESG luminal calcium during the period of shell calcification was demonstrated in
1258
several studies, the actual in vivo luminal content of ESG Ca2+, and its distribution in the
1259
lumen are less certain. Only a few studies measured ionic calcium, rather than total or
1260
diffusible calcium, in the ESG fluid (Nys et al. 1991), and all determinations were performed
1261
on uterine fluid dripped out of the vagina following artificial egg expulsion. The exposure of
1262
the fluid to the external atmosphere prior to the analysis, as well as the artificial (hormonal or
1263
mechanical) nature of the egg expulsion put some doubt on the accuracy of the observed
1264
values of ESG Ca2+. The ECPD-facilitated transport theory assumes the existence of a quite
1265
simple system consisting of a biological "membrane(s)" separating two or more well-mixed
1266
compartments. This is not necessarily the case in the calcifying ESG, where the "membrane"
1267
is composed of a variety of cells, many of which (the glandular cells) are loaded with either
1268
free or bound calcium, and that may consist of one or more compartments. Furthermore, there
1269
is also uncertainty regarding the Ca2+ concentration in the luminal zone adjacent to the Ca2+-
1270
secreting cells. It is most likely that Ca2+ is not uniformly distributed, and that its
1271
concentration changes rapidly in response to CA activity and shell calcium-carbonate
1272
formation. The latter acts as a "sink" for the secreted Ca2+ and may create a luminal Ca2+
1273
gradient within the ESG lumen that may ensure a blood-to-lumen chemical gradient
1274
facilitating the passive diffusion of Ca2+. This, together with the markedly lower relative
1275
concentration of VDR in the ESG, and the accumulated evidence for the lack of a direct
1276
major effect of vitamin D on the ESG components of transcellular Ca2+ transport, especially
42
1277
on calbindin transport (see 2.2), suggest that the active, vitamin-D-dependent transcellular
1278
transport of Ca2+ plays only a partial role in eggshell calcification. The remaining transported
1279
Ca2+ is likely to be obtained through passive paracellular mechanisms, as occurs in the
1280
intestine. Wasserman (Wasserman et al. 1991) speculated that the epithelial lining cells are
1281
those responsible for the diffusion path of Ca2+ secretion. This path utilizes both the EPD
1282
gradient (Hurwitz et al. 1970; Cohen et al. 1973; Pearson et al. 1973; Eastin et al. 1978a) and
1283
the rapid removal of the transported Ca2+ from the lumen fluid, by binding to HCO3-.
1284
The accumulated evidence suggests that HCO3- may be more important for shell
1285
formation than previously believed, and that it could be the major driving force for Ca2+
1286
transport. The evidence includes the strong association of the active secretion of HCO3- in the
1287
ESG with the transport of Cl-, active transport of Na+, and activity and expression of Na+-
1288
K+ATPase (Eastin et al. 1978a; Eastin et al. 1978b; Lavelin et al. 2001; Vetter et al. 2005).
1289
All these phenomena in the laying hen are affected by age and molt, or are associated with the
1290
egg cycle. The speculation that CA is the driving force for Ca2+ deposition is further
1291
supported by some of the observations mentioned above (see 4.1). These included: continued
1292
Ca2+ secretion when luminal Na+ was low or while its transport was prevented; the critical
1293
effects of the CA inhibitor, acetazolamide, on ESG Ca2+ transport; the lack of an effect of
1294
acetazolamide on non-laying or molting hens; and the determinant effects in situ of luminal
1295
HCO3- on Ca2+ secretion and HCO3- movement as compared with the effect of luminal Ca2+
1296
(Pearson et al. 1977; Eastin et al. 1978a; Mongin 1978; Nys et al. 1984a; Lundholm 1990;
1297
Bar et al. 1992a), whereas in vitro HCO3- affects only CA activity (see also 2.5). If this
1298
speculation is valid, then the apparently active overall CaCO3 deposition actually comprises
1299
the active transport/formation of HCO3- followed by an active-like passive transport of Ca2+
1300
along the EPD. The rapid removal of Ca2+ from the ESG lumen and its deposition in the
1301
eggshell calcium crystals would further enhance this mechanism. This hypothesis, however,
1302
has not yet been confirmed, nor does it exclude the possible involvement of transcellular
1303
transport as the major or a complementary pathway of Ca2+ transport in the ESG.
1304
5. Conclusions and speculations
1305
The available data are insufficient to support a firm hypothesis regarding the overall
1306
mechanism of calcium transport in the laying bird, i.e., the presented hypothesis is somewhat
1307
speculative. This, together with the prospects of a further drop in research on avian
1308
physiology, highlights the urgency of the need to address the uncompleted hypothesis or to
1309
offer rational speculations, at least as further working hypotheses (Fig. 8).
43
1310
1311
1312
1313
1314
1315
1316
1317
1318
1319
1320
Fig. 8. Mechanisms and factors associated with the transfer of Ca2+ from the intestine to the eggshell. The
overall phenomena involved three major transporting systems: (a) intestinal net Ca2+ absorption; (b)
eggshell gland (ESG) net secretion of Ca2+ and HCO3-; and (c) bone (medullary) remodeling. These
mechanisms are regulated by a variety of metabolic, endocrine and neurological factors (for details see
text and (Etches 1996; Nys et al. 1999; Dacke 2000; Sugiyama et al. 2001; Sharp 2005; Bar 2008; Khanal
et al. 2008).
Abbreviations: EST, estrogens; PR, progesterone; PG, prostaglandins; PTG, parathyroid gland; PTH,
parathyroid hormone; 1,25-D3, 1,25-dihydroxy vitamin D3; CA, carbonic anhydrase; MEDUL.,
medullary; PBP, plasma-calcium binding proteins. Above the dotted black line are given the events
associated with sexual (marked in the figure with numbers within parentheses: #: 1,2,4,5,10-15,18-21)
44
1321
1322
1323
1324
1325
1326
1327
1328
1329
1330
1331
1332
1333
1334
1335
1336
1337
1338
1339
1340
1341
1342
1343
1344
1345
1346
1347
1348
1349
1350
1351
maturation and the early stages of egg formation and plumping (marked in the figure with numbers within
parentheses: #: 2-5,8-10,12-14,16?,18,19?20,22,23); below it are given those associated with calcification
(marked in the figure with numbers within parentheses: #: 2,4,6-22,24-26). Light- and dark-gray frames
represent transporting and endocrine organs, respectively; black arrows represent ion transport; gray
arrows represent endocrine activity, gray-open arrows represent not-yet established endocrine activity;
gray dotted arrows represent non-endocrine factors associated with the regulation or sensing activity.
(1) Once the ovary is developed it (2) secrets the gonadal hormones; among them EST that together
with other gonadal hormones induce oviduct development and maintenance, acts as anti apoptotic mean
and stimulate (3) egg-white proteins synthesis. In addition, (4) EST induce liver formation of PBP and (5)
induce (together with testosterone) medullary bone formation. (6) EST may have also a not-yetestablished specific effect on shell calcification. (7) PR affects specifically shell calcification and
calbindin mRNA synthesis and appears to be a rational candidate for the “off” signal for shell
calcification. (8) PG, formed in the follicles and (8a) in the oviduct, is believed to regulate (9) oviduct
muscle contraction and egg oviposition (other hormones such as parathyroid hormone related peptide,
either of autocrine or paracrine origin, or arginine vasotocin or oxytocin may also be involved in this
activity). (10) The reduced plasma Ca2+ resulted from its binding to the PBP and/or its deposition in the
medullary bone, and/or, to much greater extent, in the eggshell induces PTH secretion by the PTG. (11)
PTH, as well as (12) the lower plasma (extracellular) Ca 2+ (13) induce the formation of renal 1,25-D3,
whereas high extracellular Ca2+ reduces 1,25-D3 synthesis and induces renal calbindin synthesis. (14)
1,25-D3 induces intestinal Ca2+ absorption (see also Fig. 7) and (15) bone calcium mobilization. (16) 1,25D3 may have also an effect on ESG CA (not-yet-established) and (17) on the transfer of Ca 2+ into the shell
gland lumen (most of the evidence reject this hypothesis). (18) 1,25-D3 down regulates its own synthesis
by the kidney and (19) down regulates PTH formation by the PTG. (20) Both hormones (PTH and 1,25D3), as well as the extracellular Ca 2+, regulate renal reabsorption of Ca2+ and consequently urinary
calcium. (21) PTH (and 1,25-D3; see also 15) affects bone remodeling (osteoclast activity). (22) Pressure
sensitivity to mechanical strain resulted from egg white formation in the magnum and egg swelling
(plumping) in the ESG (23) induces OPN mRNA formation in the isthmus and (24) the circadian
synthesis of several other mRNAs in the ESG. (25) A Ca 2+-transport-related factor(s) induces ESG
calbindin and few other ESG mRNAs synthesis. (26) H+ resulted fro ESG-CA induces acidosis and
consequently calcium solubility in the gizzard and the intestinal lumen.
1352
The overall phenomenon is acceleration of Ca2+ flow from the gut lumen to the ESG lumen,
1353
where the eggshell is formed during the later phases of the egg cycle. Most likely, this flow is
1354
primarily driven by ESG-CA activity that results in high HCO3- content that, in turn, "sucks
1355
out" calcium from the intestinal lumen via the blood and ESG cells, and deposits it in the
1356
shell crystals. In the intestine, where the capacity to transport Ca2+ corresponds, in most cases,
1357
to the calbindin content (Bar et al. 1979a; Bar et al. 1979b), the transcellular pathway appears
1358
to provide an additional means to overcome low calcium intake, but the major driver remains
1359
the ECPD and its response to the variations in blood and intestinal lumen concentrations of
1360
Ca2+ during the egg cycle. Acidosis/H+ formation that result from CA activity during shell
1361
calcification may benefit the ECPD contribution to the paracellular Ca2+ transport, through
1362
their effect on calcium solubility in the gizzard and the intestinal lumen (see 3.2; 3.3.2.2;
1363
3.3.2.3; (Mongin 1976b; Mongin 1976a)). This may explain some of the discrepancy between
1364
calbindin content and the intestinal capability to absorb Ca+2 under certain conditions, such as
1365
onset of production (see 2.2; 3.1) or during shell calcification. It may also explain the specific
1366
effect of exogenous 1-hydroxylated active derivatives of vitamin D, which is observed almost
1367
exclusively during the period of shell calcification (see 2.2; 3.3.2). This supports the idea that
1368
intestinal paracellular Ca2+ transport is also dependent on vitamin D. The above-mentioned
1369
suggestion is further supported by the recent finding that calbindin-D9K is not required for
45
1370
vitamin D3-mediated Ca2+ absorption in the mammalian small intestine (Akhter et al. 2007;
1371
Benn et al. 2008).
1372
In the ESG, although TRPVs were not yet identified, the presence of the other two
1373
components (PMCA and calbindin) of transcellular transport Ca2+, the presence of TRPVs in
1374
the mammalian uterus and placenta, the localization of PMCA (see 3.2, 4.2, 4.4), and the
1375
apparently "uphill" transport of Ca2+ that occurs in the ESG, support the idea that Ca2+ is
1376
transported via the transcellular pathway. However, the lack of an effect of vitamin D on the
1377
ESG transport of Ca2+, the plasma-to-ESG lumen positive EPD, the lack of solid information
1378
on the Ca2+ concentrations in the luminal zone adjacent to the Ca2+-secreting cells, and the
1379
obvious and critical involvement of CA in this procedure, suggest that the mechanisms there
1380
could not be easily explained solely in terms of a simple mechanism of transcellular Ca2+
1381
transport. If that were the case, the "active" Ca2+ transport would reflect the energy-dependent
1382
CA activity, which is also involved in shell deposition in the ESG, rather than true active Ca2+
1383
transport. The Ca2+ transport takes place mostly, or at least to a great extent, via the
1384
paracellular routes, rather than via the energy-dependent transcellular Ca2+ transport.
1385
With regard to the paracellular transport, ESG calbindin, which is related to shell Ca2+
1386
mass (Bar et al. 1984b; Nys et al. 1986b; Bar et al. 1988; Bar et al. 1992a; Bar et al. 1992b;
1387
Bar et al. 1999; Goto et al. 2002c), may provide buffering capacity that prevents the
1388
accumulation of excessive cellular Ca2+, or acts as an anti-apoptosis, rather than a
1389
transporting factor.
1390
The hypothesis that calbindin, a major component of the transcellular transport of
1391
calcium, has differing roles in Ca2+ transport in the intestine and in the ESG is strengthened
1392
by the differing roles played by vitamin D in calbindin synthesis by the two transporting
1393
organs (see 2.2).
1394
The overall mechanism and its hormonal control develop during the birds’ growth and
1395
during maturation, before the onset of egg laying, and then undergo accelerated development
1396
during the egg cycle. The early pre-laying regulation involves the growth and metabolism
1397
hormones, induction of the development of the functional ESG by the hypothalamus-
1398
pituitary-gonadal (neuroendocrine) hormones the formation of yolk- and plasma-calcium-
1399
binding proteins in the liver, and the establishment of the calcium reservoirs in the bones,
1400
especially the specific medullary bone. Because of the increased demands for Ca2+ for these
1401
reservoirs, the calcium-regulating hormones induce the development of intestinal absorptive
1402
capacity for calcium. The calcium-regulating and the gonadal hormones appear also to be
1403
involved in the development of the high ESG-CA capacity and, most likely, also in the
1404
development of ESG-PMCA and TPRVs (if occur there). However, the diurnal variation in
1405
calcium transport by the ESG is unlikely to be dependent on the calcium-regulating hormones
46
1406
(see 3.3). On the other hand, the plasma concentrations of many gonadal and neuroendocrine
1407
hormones fluctuate in close temporal association with shell formation during the egg cycle,
1408
and may be responsible for the variation in calcium transport or CA activity. Progesterone
1409
concentration peaked (Doi et al. 1980; Johnson et al. 1980; Nys et al. 1986a; Braw-Tal et al.
1410
2004) 2 to 6 h before termination of shell calcification, and a single i.m. injection of
1411
progesterone, but not of estrogen or testosterone, given while the egg was in the magnum,
1412
markedly inhibited shell calcification of the formed egg, delayed its oviposition (Nys 1987;
1413
Bar et al. 1996; Goto et al. 2002b), and inhibited calbindin gene transcription in the ESG but
1414
not in the intestine) (Bar et al. 1996; Goto et al. 2002b). Estrogen has only a tiny effect on
1415
ESG calbindin (See 2.2), therefore, the marked effect of progesterone could not be a result
1416
only of its anti-estrogenic (Bruns et al. 1988; Corradino 1993) activity. This suggests that
1417
progesterone may play a specific role in the "turn-off" signal that terminates shell
1418
calcification. Less evidence is available concerning the "turn on" signal for shell calcification:
1419
this signal, too, may be dependent, in an as yet undefined way, on the gonadal or
1420
neuroendocrine hormones, but it may also be initiated by the mechanical strain developed
1421
during "egg white" secretion in the magnum or during its swelling ("plumping") in the ESG
1422
just after the movement of the shell-less egg from the isthmus to the ESG (reviewed by
1423
(Solomon 1991; Etches 1996; Johnson 2000)). This hypothesis is supported by the findings
1424
that ESG Ca2+ secretion in situ during the period of shell calcification (predicated on the basis
1425
of the earlier ovulation) is further stimulated by the presence of an egg (or an egg-like insert)
1426
in the ESG (see 4.1). It was found that: an Na+ pump has a role in the ESG-CA activity (see
1427
also 2.5); that mechanical strain appears to regulate molecular events in the ESG, such as the
1428
expression of Na+-K+-ATPase (Lavelin et al. 2001) and of other genes (Lavelin et al. 1998;
1429
Lavelin et al. 2000; Lavelin et al. 2002); and mechanoreceptor candidates were already
1430
considered to be involved in another calcium-transporting tissue, i.e., the bone (reviewed in
1431
(Rubin et al. 2006) and others). In light of these findings, the possibility of a specific role of
1432
the mechanical strain that results from the formation of egg white in the magnum and
1433
"plumping" in the initiation of shell formation should not be ignored. Such a combined
1434
mechanism (pressure and the endocrine cycle) may be involved in the initiation of shell
1435
formation, via the completion of the OPN-containing mammillae on the egg outer membrane,
1436
where the seeding of the calcium crystals of the calcified shell is initiated.
1437
Although some aspects of the above speculation remain to be proved, such a hypothesis,
1438
that aims to account for the elevated transport of Ca2+ in the ESG and intestine during shell
1439
formation, should be considered seriously.
1440
47
1441
Acknowledgments
1442
Contribution from the Institute of Animal Science, Agricultural Research Organization, the
1443
Volcani Center, Bet Dagan, Israel: No. 532-08.
1444
The encouragement and comments of Prof. S. Yahav and the comments of Dr. Pines, ARO
1445
are acknowledged with appreciation.
1446
1447
1448
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