Embryo ch 6
GASTRULATION
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Gastrulation – process that establishes all three germ layers (endoderm, mesoderm, ectoderm)
– begins with formation of primitive streak on surface of epiblast (narrow groove with slightly
bulging regions on either side)
o Primitive node – cephalic end of primitive streak; consists of a slightly elevated area
surrounding the primitive pit
Cells of the epiblast migrate towards the primitive streak, where they become flask-shaped,
detach from epiblast, and slip beneath it (process called invagination)
Fibroblast growth factor 8 (FGF8) – synthesized by streak cells to control cell migration and
specification – downregulates E-cadherin, a protein that normally binds epiblast cells together
Once cells invaginate, some displace the hypoblast, creating the embryonic endoderm; some go
between epiblast and newly created endoderm to make mesoderm; cells remaining in epiblast
form ectoderm
Eventually cells moving between epiblast and hypoblast layers go beyond margin of the disc and
establish contact with the extraembryonic splanchnic mesoderm covering the yolk sac and
amnion – in cephalic direction, they pass on each side of prechordal plate, which forms between
tip of notochord and oropharyngeal membrane
FORMATION OF NOTOCHORD
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Prenotochordal cells invaginating in primitive node move forward cranially until they reach
prechordal plate, where they become intercalated in hypoblast, so for a short time, the
midline consists of 2 cell layers that form notochordal plate
As hypoblast replaced by endoderm cells moving in at streak, cells of notochordal plate
proliferate and detach from endoderm, forming a solid cord of cells (definitive notochord) –
cranial end forms first
Neurenteric canal – temporary connection between amniotic and yolk sac cavities at point
where pit forms indentation in epiblast
Cloacal membrane – formed at caudal end of embryonic disc – consists of tightly adherent
ectoderm and endoderm cells with no intervening mesoderm
When cloacal membrane appears, posterior wall of yolk sac forms small diverticulum that
extends into connecting stalk – diverticulum called allantoenteric diverticulum or allantois
ESTABLISHMENT OF BODY AXES
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Occurs during gastrulation
Anteroposterior axis signaled by cells at anterior margin of embryonic disc called anterior
visceral endoderm (AVE)
o AVE expresses genes essential for head formation and secreted factors cerberus and
lefty, which inhibit nodal activity in cranial end of embryo
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o Cranial end established before gastrulation
Regions of epiblast that migrate and ingress through primitive streak have been mapped and
their ultimate fates determined
o Cells that ingress through cranial region of node become prechordal plate and
notochord
o Cells migrating at lateral edges of node and form cranial end of streak become paraxial
mesoderm
o Cells migrating through midstreak region become intermediate mesoderm
o Cells migrating through more caudal part of streak form lateral plate mesoderm
o Cells migrating through caudal most part of streak contribute to extraembryonic
mesoderm
GROWTH OF EMBRYONIC DISC
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Embryonic disc, initially flat and round, becomes elongated with broad cephalic end and narrow
caudal end
Growth and elongation of cephalic part of disc are caused by continuous migration of cells from
primitive streak region in cephalic direction
After 4th week, primitive streak shows regressive changes, rapidly shrinks, and disappears
Differentiation in caudal part of embryo begins by end of 4th week
TERATOGENESIS ASSOCIATED WITH GASTRULATION
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Beginning of third week of development is highly sensitive stage for teratogenic insult because
of fate maps being made for caudal functions (brain anlage, eyes, etc.)
Holoprosencephaly (failure of forebrain to develop properly) can be cause by high alcohol doses
at this stage – two ventricles often merge into single ventricle, and eyes are close together
(hypotelorism)
Caudal dysgenesis (sirenomelia) – insufficient mesoderm is formed in caudal most region of
embryo, and thus abnormalities in lower limbs, urogenital system, and lumbosacral vertebrae
occur – can present in hypoplasia, fusion of lower limbs, vertebral abnormalities, renal agenesis,
imperforate anus, and anomalies of genital organs – can be caused by diabetic mother
Situs inversus – transposition of viscera of thorax and abdomen
Laterality sequences – conditions where patients do not have complete situs inversus, but
appear to be predominantly bilaterally right or left-sided (i.e., those with left-sidedness have
polysplenia while those with right-sidedness can have asplenia or hypoplastic spleen)
Serotonin – important for establishing laterality – disruption of serotonin signaling can cause
situs inversus, dextrocardia, and heart defects
o Children born to mothers who take antidepressants from SSRI class (selective serotonin
reuptake inhibitors) have increased risk of heart malformations
Remnants of primitive streak persisting in sacrococcygeal region proliferate and form tumors
called sacrococcygeal teratomas, which consist of tissues from all 3 germ layers – most common
tumor in newborns
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Teratomas may arise from primordial germ cells that fail to migrate to gonadal ridge
FURTHER DEVELOPMENT OF TROPHOBLAST
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Mesodermal cells penetrate core of primary villi and grow toward decidua – this new structure
called secondary villi
By end of 3rd w eek, mesodermal cells in core of villus begin to differentiate into blood cells and
small blood vessels, forming villous capillary system – villus now called tertiary villus or definitive
placental villus
Vessels branch and begin to connect to ones in circulatory system and placenta, so when heart
begins to beat in 4th week, villous system is ready to supply embryo proper with essential
nutrients and oxygen
Cytotrophoblastic cells in villi penetrate into overlying syncytium until they reach maternal
endometrium, where they establish contact with extensions from neighboring villi, forming thin
outer cytotrophoblast shell
Outer cytotrophoblast shell gradually surrounds trophoblast entirely and attaches chorionic sac
firmly to maternal endometrial tissue
Villi extending from chorionic plate to decidua basalis are called stem (anchoring) villi, while
those that branch from sides of stem villi are free (terminal) villi
By day 19-20, embryo is attached to trophoblastic shell by narrow connecting stalk that will
become umbilical cord
EMBRYONIC PERIOD
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3rd to 8th week of pregnancy
Time in which germ layers differentiate and form organs
Notochord and prechordal mesoderm induce overlying ectoderm to thicken and form neural
plate, whose cells make up the neuroectoderm – their induction represents initial event in
process of neurulation
Neurulation – process whereby neural plate forms neural tube
By end of 3rd week, lateral edges of neural plate become elevated to form neural folds, and
depressed midregion forms neural groove
Gradually, neural folds approach each other in the midline, where they fuse, beginning in the
cervical region and proceeding cranially and caudally – this is formation of neural tube
o Before fusion is complete, cephalic and caudal ends of neural tube communicate with
amniotic cavity by way of anterior and posterior neuropores
o Closure of cranial neuropores occurs ~day 25 and closure of posterior neuropore closes
~day 28
Closed tubular structure with narrow caudal portion becomes spinal cord, and broader cephalic
portion characterized by dilations becomes brain vesicles
Neural crest – cells at lateral border of neural folds that begin to dissociate from their neighbors
– undergo epithelial-to-mesenchymal transition to enter underlying mesoderm
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Crest cells from trunk region neuroectoderm after closure of neural tube and migrate
either
 Dorsal pathway through dermis, where they enter ectoderm through holes in
basal lamina to form melanocytes in skin and hair
 Ventral pathway through anterior half of each somite to become sensory
ganglia, sympathetic and enteric neurons, Schwann’s cells, and cells of adrenal
medulla
o Neural crest cells also form and migrate from cranial neural folds, leaving neural tube
before closure to contribute to craniofacial skeleton, neurons for cranial ganglia, glial
cells, and melanocytes
o Sometimes nicknamed fourth germ layer
By time neural tube is closed, two bilateral ectodermal thickenings become visible
o Otic placodes – invaginate and form otic vesicles, which develop into structures for
hearing and maintenance of balance
o Lens placodes – invaginate and form lenses of eyes during 5th week
NEURAL TUBE DEFECTS (NTDs)
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If neural tube fails to close in cranial region, most of brain fails to form, and anencephaly occurs
– lethal defect
If closure of neural tube fails anywhere caudal of neck, this is called spinal bifida – most
common site is lumbosacral region – children lose degree of neurological function based on
spinal cord level of lesion and severity
o Has been shown to have a connection to folic acid intake of mother
DERIVATIVES OF MESODERMAL GERM LAYER
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By day 17, cells close to the midline proliferate and form thickened plate of tissue known as
paraxial mesoderm
More laterally, mesoderm remains thin and is called lateral plate, which divides into 2 layers
o Somatic (parietal) mesoderm layer – continuous with mesoderm covering amnion
o Splanchnic (visceral) mesoderm layer – continuous with mesoderm covering yolk sac
Lateral plate mesoderms line intraembryonic cavity, which is continuous with extraembryonic
cavity on each side of embryo
Intermediate mesoderm connects paraxial and lateral plate mesoderm
By beginning of 3rd week, paraxial mesoderm begins to be organized into segments called
somitomeres – first appears in cephalic region of embryo and formation proceeds caudally
o Each somitomeres consists of mesodermal cells arranged in concentric whorls around
center of unit
o Somitomeres in head region form in association with segmentation of neural plate into
neuromeres
o From occipital region caudally, somitomeres organize into somites – first pair arises
around day 20
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o At end of 5th week, there are 42-44 pairs of somites
When somites first form, they exist as ball of mesoderm and then undergo epithelization and
arrange themselves in a donut shape and medial walls of somite lose epithelial characteristics,
become mesenchymal again, and shift position to surround neural tube and notochord (these
cells form sclerotome that will differentiate into vertebrae and ribs)
Cells at dorsomedial and ventrolateral edges of upper region of somite form precursors for
muscle cells, while cells between those edges form dermatome
o Cells from both muscle precursor groups become mesenchymal again and migrate
beneath dermatome to create dermomyotome – ultimately form dermis for skin of back
and muscles for back, body wall (intercostals), and some limb muscles
Cells from ventrolateral edge of somite migrate into parietal layer of lateral plate mesoderm to
form most of musculature of body wall and most of limb muscles
Intermediate mesoderm differentiates into urogenital structures
o In cervical and upper thoracic regions, it forms segmental cell clusters (future
nephrotomes)
o More caudally, it forms unsegmented mass of tissue (nephrogenic cord)
Lateral plate mesoderm splits into parietal (lines intraembryonic cavity) and visceral layers
(surrounds organs)
Mesothelial (serous) membranes – thin membranes formed by mesoderm cells of parietal layer
surrounding intraembryonic cavity – will eventually line peritoneal, pleural, and pericardial
cavities and secrete serous fluid
Mesoderm cells of visceral layer form thin serous membrane around each organ
BLOOD AND BLOOD VESSELS
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Arise from mesoderm
Blood vessels form by
o Vasculogenesis – vessels arise from blood islands
o Angiogenesis – vessels sprout from existing vessels
First blood islands appear in mesoderm surrounding wall of yolk sac at 3 weeks and slightly later
in lateral plate mesoderm and other regions
o These islands arise from mesoderm cells induced to form hemangioblasts
Definitive hematopoietic stem cells derived from mesoderm surrounding aorta near developing
mesonephric kidney (aorta-gonad-mesonephros (AGM) region) – these cells colonize liver, and
stem cells from the liver colonize the bone marrow in the 7th month and liver loses blood
forming function
CAPILLARY HEMANGIOMAS
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Abnormally dense collections of capillary blood vessels that form most common tumors of
infancy
May occur anywhere but most often associated with craniofacial structures
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May be focal or diffuse – diffuse lesions cause more secondary complications like ulcerations,
scarring, and airway obstruction
Caused by overly expressed regulators of blood vessel formation
DERIVATIVES OF ENDODERM
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With development and growth of brain vesicles, embryonic disc begins to bulge into amniotic
cavity
Lengthening of neural tube causes embryo to curve into fetal position as head and tail regions
move ventrally – simultaneously, two lateral body wall folds form and move ventrally to close
ventral body wall – as this occurs, it pulls amnion down with them such that embryo lies w/in
amniotic cavity
o Ventral body wall closes completely except for umbilical region where connecting stalk
and yolk sac duct remain attached
As result of cephalocaudal growth and closure of lateral body wall folds, a continuously larger
portion of endoderm is incorporated into body of embryo to form gut tube
o Midgut communicates with yolk sac by way of broad stalk (vitelline duct) – starts short
and wide but grows long and narrow
o Foregut temporarily bounded by ectodermal-endodermal membrane (oropharyngeal
membrane) that separates stomadeum (primitive oral cavity from ectoderm) from
pharynx (from endoderm) – in 4th week, oropharyngeal membrane ruptures,
establishing open connection between oral cavity and primitive gut
o Hindgut terminates temporarily at cloacal membrane, which separates upper part of
anal canal (from endoderm) from lower part (proctodeum, formed by invaginating pit
lined by ectoderm) – membrane breaks down in week 7 to create open anus
Cephalocaudal grwtoh and lateral folding partially incorporates allantois into body of embryo,
forming cloaca – distal portion of allantois remains in connecting stalk
o By 5th week, yolk sac duct, allantois, and umbilical vessels restricted to umbilical region
EXTERNAL APPEARANCE DURING SECOND MONTH
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At end of 4th week, embryo has ~28 somites – main external features are somites and
pharyngeal arches – thus age of embryo counted by somites
During 2nd month, age of embryo indicated by crown-rump length (CRL) and is expressed in mm
o CRL – measurement from vertex of skull to midpoint between apices of buttocks
By beginning of 5th week, forelimbs and hindlimbs appear as paddle-shaped buds
o Forelimbs are dorsal to pericardial swelling between 4th cervical and 1st thoracic somites
o Hindlimbs appear just caudal to attachment of umbilical stalk at level of lumber and
upper sacral somites
Limbs form flat circles for hands and feet, then rays (precursors to fingers and toes) begin to
form – while these form, a second constriction divides limb portion of bud into two segments
BIRTH DEFECTS
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Most major organs and systems formed during 3rd and 8th weeks
This period is critical for normal development and called organogenesis or embryogenesis
Period when most gross structural birth defects induced
HUGE because mother may not realize she is pregnant during start of this time