NS/BioAP475
Mechanisms Underlying Mammalian Developmental Defects
Feb. 11, 2002
Maternal-Placental Metabolism
The placenta constitutes the maternal-fetal interface. The placenta is comprised of two components, a
fetal portion that develops from the chorionic sac (trophoblast derivatives) and a maternal portion that is
derived from the endometrium. The chorion forms a covering that surrounds the embryo, amnion, and
yolk sac. The placenta is the primary site of nutrient and gas exchange between the mother and fetus,
and both the mother and fetus contribute to fetal circulation. Fetal blood reaches the placenta through
two umbilical arteries. While fetal circulation is confined to blood vessels, maternal blood is free
flowing and not confined to vessel walls (150 ml reservoir exchanges 3-4 times a minute).
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Placental Functions:
1. Protection
pathogens
maternal immune system
2. Endocrine Organ
Steroid hormones, growth factors, cytokines.
3. Exchange Function:
a. Metabolism-Nutrition, Nutrient Processing
b. Respiration - almost as efficient as the lung in gas exchange, limited by blood flow
c. Excretion
Endocrine secretion/Placental Hormones: The placental syncytiotrophoblasts produces both protein
and steroid hormones.
Human Chorionic Ganadotropin (hCG). A glycoprotein similar to luteinizing hormone (LH).
It maintains corpus luteum and its production of estrogen and progesterone and thereby prevents
the onset of menstrual periods.
- synthesized prior to implantation.
- common test for pregnancy since its synthesis is unique to pregnancy.
- maternal serum concentrations peak at week 8 then decline. By the first trimester, placenta
produces enough progesterone and estrogen to maintain pregnancy.
Progesterone and Estrogen. After 7 weeks, the placenta is the primary source of steroid
hormones. These hormones are necessary for the initiation and maintenance of pregnancy and
are synthesized from acetate and cholesterol. Nearly all estrogen enters the maternal circulation.
Estrogen promotes phospholipid turnover in the maternal liver. Ninety percent of progesterone
enters maternal circulation.
Chorionic thyrotropin and chorionic corticotropin - secreted into maternal blood stream and
stimulate changes in metabolism and cardiovascular function of the mother. Ensures appropriate
levels of nutrients are available for the mother.
Chorionic somatomammotropin - (human placental lactogen) similar structure to human growth
hormone, influences growth, lactation, lipid and carbohydrate metabolism. It is similar to and
may substitute for pituitary growth hormone. It regulates maternal blood glucose levels and
IGF-1 synthesis and secretion. hPL is secreted when maternal plasma glucose levels are low and
stimulates the expression/secretion of maternal IGF-1 to enhance fetal glucose and amino acid
uptake. Also stimulates maternal gluconeogenesis in the liver.
- Unique to placenta
- Member of growth hormone family but more similar to growth hormone than prolactin;
it binds to growth hormone receptor.
- hPL is 87% similar to human growth hormone.
- Modulates fetal and maternal metabolism in the liver. Increases lipolysis and glucose
production in the mother.
- no hPL receptor has been isolated, but there is evidence for its existence. hPL
receptors have been identified in both fetal liver and skeletal muscle. The binding sites
for GH and hPL appear to be distinct.
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NS/BioAP475
Mechanisms Underlying Mammalian Developmental Defects
Feb. 11, 2002
GH Receptor
GH is a member of the cytokine receptor superfamily
3 domains
1. 346 AA extracellular domain that dimerizes and binds GH.
2. A short transmembrane domain.
3. 350 AA intracellular domain required for signal transduction.
The binding of GH to its receptor initiates a signal transduction pathway involving the tyrosine
phosphorylation of multiple cellular peptides. This event activates Janus Kinase 2 (JAK2) as the growth
hormone activated tyrosine kinase and the first step in the signal transduction of GH.
GH and hPL stimulate phosphorylation of insulin receptor substrate 1- (IRS-1), which is critical for
insulin signaling. GH and hPL stimulate phosphorylation of cytoplasmic transcription factors
designated as signal transducer/activator of transcription (Stat) proteins (Stat-1 and Stat-3). Causes
transcription of their target genes.
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Exchange Functions: The placenta is an 11m2 exchange surface at the time of human birth. Mother
delivers oxygen and nutrients, fetus delivers fetal waste (urea, bilirubin) and CO2. Nutrient transport
occurs by several processes. Gases, electrolytes, and water pass by diffusion. The placenta is
selectively permeable to the sugar glucose, but not fructose. Amino acids and vitamins and iron (in the
form of transferrin) and are transported by specific receptors. Proteins, (including antibodies) are
transported slowly by pinocytosis. IgGs are especially important as the fetus cannot synthesize large
quantities of these agents and maternal antibodies give immunity to disease including small pox,
diphtheria and measles. There are three primary mechanisms for transport of nutrients between the
placenta and fetus:
1.
2.
3.
4.
Simple diffusion - move across concentration gradient
Facilitated diffusion - transporter that can neutralize electrical charges
Active transport - transports against a gradient; requires energy
Pinocytosis - endocytosis by capturing extracellular fluid; for large molecules.
Disruption of placental function; Effects on fetal development:
1. Fetal “starvation” resulting from general maternal malnutrition or catastrophic placental
developmental anomalies. Can result in low birth weight, premature delivery or death.
2. Fetal single nutrient deficiencies resulting from single gene or single function disruption, or
maternal deficiencies of a single nutrient. Can result in developmental defects, low birth weight
premature delivery and death.
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NS/BioAP475
Mechanisms Underlying Mammalian Developmental Defects
Feb. 11, 2002
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Metabolic/Nutrition Functions of the Placenta:
Example I: Fetal “starvation” can result from maternal malnutrition or catastrophic placental
developmental anomalies. Esx1 is ax X-linked, paired-like homeobox gene whose expression is limited
to extraembryonic tissues (chorionic ectoderm, visceral yolk sac endoderm and the labyrinthine
trophoblasts of the chorioallantoic placenta) and is an imprinted regulator of placental morphogenesis
and trophoblast differentiation.. In mice and marsupials, the paternal X chromosome is preferentially
inactivated. Deletion of Esx1 in males and females who’s X-chromosome was maternally derived
results in significantly smaller pups compared to both wild type pups and female pups carrying the
deleted allele on the paternally derived X-chromosome. All pups achieved the same weight at 13.5 dpc,
but differences were seen by 16.5 dpc. thereby indicating that Esx1 is critical for chorioallantoic
placenta formation, but not the choriovitelline placenta. However, by maturity, all pups achieved the
same weight, providing evidence for “catch up” growth. Growth retarded Esx1 -/- mice contained larger
and heavier placenta than control animals. Analysis of the placenta indicated that the labyrinthine layer,
where fetal-maternal metabolic exchange occurs, was abnormal. This mouse model mimics human
intrauterine growth retardation associated with abnormal placental function, which leads to low birth
weight babies. Such children have a high incidence of chronic disease later in life.
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NS/BioAP475
Mechanisms Underlying Mammalian Developmental Defects
Feb. 11, 2002
Example II, Glucose transport: Single nutrient deficiencies can result from single gene, single
function disruption, or maternal single nutrient malnutrition:
Glucose (the principal carbohydrate delivered from the mother to fetus) is actively transported from
maternal circulation to the placenta, and transported to the fetus by facilitative diffusion across a
concentration gradient. The placenta also has a high metabolic demand, and consumes 2/3 of all oxygen
and half of the glucose delivered from uterine circulation. The placenta requires this energy to carry out
its many functions. The rate of glucose transfer from mother to fetus is dependent upon maternal
glucose concentrations. The maternal-fetal arterial glucose concentration gradient is the driving force
that determines placental glucose uptake and transfer to the fetus. The glucose facilitative transporter is
Glut1. It is specific for glucose and transports glucose 10,000 times faster than transport by diffusion.
However, GluT1 has a Km of 25 mM glucose, higher than maternal glucose concentrations.
Hypoglycemia-GluT 1 expression is unaffected by hypoglycemia, but down-regulated during
hyperglycemia. During hypoglycemia, the fetes can perform gluconeogenesis to supply both fetal and
placental tissues in the absence of maternal glucose.
Hyperglycemia - Elevated maternal glucose elevates fetal and placental glucose. It also leads to
increased fetal insulin secretion in the human, but not in animal models.
GluT1 is found on both the maternal-facing microvillus trophoblast membrane and the fetal-facing basal
trophoblast membrane. This arrangement allows bi-directional transport of glucose to the placenta from
both the maternal (essentially irreversible) and fetal plasma glucose (can be reversible) pools. In mice,
but not humans, Connexin26 transports glucose between syncytiotrophoblastic layer 1 and
syncytiotrophoblastic layer II through the gap junction. Connexin26 is a selective cell-to-cell channel
(gap junction) that enables exchange of small diffusible molecules in the labyrinthine. Cx26 deletion is
embryonic lethal at mid gestation (11 dpc.) in mice with the maternal glucose transport decreased by
60%, whereas defects in human CX26 show no phenotype due to differences in placental anatomy. The
embryos are smaller at 10 dpc and essentially starve to death without any malformations, at a time when
the chorioallantoic placenta replaces yolk sac function. .
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Rossant, 2001
Gabreil et al., 1998
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Mechanisms Underlying Mammalian Developmental Defects
Feb. 11, 2002
Gabreil et al., 1998
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Gabreil et al., 1998
Example III: Placental defects leading to fetal developmental anomalies: Lipid Transport and PPARγ
The placenta has specific transporters for specific fatty acids, and can obtain lipids from maternal
lipoproteins. Fatty acids are transferred both by specific transporters and by simple diffusion across a
maternal to fetal concentration gradient. Triglycerides do not cross the placenta, but the fetal liver can
synthesize triglycerides from maternal fatty acids. The placenta can deliver lipids to the fetus as free
fatty acids but there is no strong evidence for placental assembly of lipoproteins. The fetal liver
synthesizes cholesterol, although it may obtain maternal cholesterol as well. Both maternal and fetal
plasma fatty acid/lipid compositions are similar; and fatter human fetuses develop in pregnancies with
high maternal plasma lipids. This suggests the fetal serum lipid concentrations are dependent upon
maternal lipid concentrations, a phenomenon that seems to be unique to humans.
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NS/BioAP475
Mechanisms Underlying Mammalian Developmental Defects
Feb. 11, 2002
PPARγ is a nuclear hormone receptor that requires a lipid ligand for activation (prostaglandin J2, or the
drug thiazolidinedione (TZD, a drug used to treat diabetes, type II)). PPARγ regulates genes involved in
lipid homeostasis, but also is required for epithelial differentiation of trophoblasts and therefore proper
placental vascularization. Homozygous deletion of PPARγ is embryonic lethal at 12.5 dpc due to
defective placental vascularization and myocardial thinning. However, PPARγ -/- embryos develop to
term without cardiac defects when provided with a normal placenta, indicating a placenta/cardiac axis is
necessary for normal subepicardial myocytes proliferation and differentiation (in PPARγ -/- embryos,
myocytes differentiate prematurely leading to reduced proliferation in the ventricular wall and have
abnormal mitochondria). Cardiomyopathies are the most common facilities during the first year of
human life, and a leading cause of spontaneous late term abortions, the “myocardial wall syndrome”.
The heart seems to be the only organ affected in this manner by placenta dysfunction.
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Example IV: Amino Acids.
Amino acid transport provides a source of both nitrogen and metabolic fuel for the fetus and placenta, as
well as the building blocks for protein synthesis. Amino acid transport occurs by active energy
dependent transporters. The transport energy derived from transmembrane Na+, K+, Cl- and H+
electrochemical gradients. Active transport is necessary as placental and fetal plasma amino acid
concentrations exceed that found in maternal tissue. In fact, maternal hypoglycemia can inhibit fetal
amino acid transport. Several specific transporters exist, some specific for individual amino acids, some
for classes of amino acids (i.e. hydrophobic amino acid transporters). The placenta is not simply an
amino acid pump, but regulates both maternal import and placental export (to the fetus). Some amino
acids, like glutamine, are transported directly to the fetus or can undergo placental metabolism. Other
amino acids like leucine are metabolized to other products (L à α-ketoisocaproic acid) for delivery to
the fetus. Fetal-placental serine and glycine metabolism is very unique. Glycine is a required amino
acid for the fetus and is derived from serine in the placenta. The fetus exports large amounts of serine
for placental metabolism, including serine for the synthesis of glycine. The fetus does not uptake
placental serine. The role of this unique shuttle is unknown.
The placenta also plays a key role in regulating ammonium supply for the fetus.
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NS/BioAP475
Mechanisms Underlying Mammalian Developmental Defects
Feb. 11, 2002
References:
Hay, W. W. (1994) Placental transport of nutrients to the fetus. Horm. Res. 42, 215-222.
Anthony, R. V., Fanning, M. D., and Richer, L. C. (1997) Development of hormone receptors within the
fetus in placenta function and fetal nutrition. Vevey/Lippincott-Raven Publishers, Phila. PA.
Garnica and Chan. (1996) The role of the placenta in fetal nutrition and growth Journal of the American
College of Nutrition. 15, 206-222.
Barak et. Al. (1999) PPARγ is required for placental, cardiac and adipose tissue development. Molecule
Cell. 4, 585-595.
Rossant J. and Cross, J. C. (2002) Placental development: lessons from mouse mutants. Nature Review
Genetics. 2, 538-548.
Gabriel et al. (1998) Transplacental uptake of glucose is decreased in embryonic lethal Connesin26deficient mice. J. Cell. Biol. 140, 1453-1461.
Li and Behringer (1998) Esx1 is an X-chromosome-imprinted regulator of placental development and
fetal growth. Nature Genetics. 20, 309-311.
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