Neurulation, Somitogenesis,
General Body Plan, and
Fetal Membranes
J. Matthew Velkey
454A Davison, Duke South Green Zone
matt.velkey@duke.edu
Basic structure at 4 weeks
The three germ layers are formed at gastrulation
Ectoderm: outside, surrounds other
layers later in development,
generates skin and nervous
tissue.
Mesoderm: middle layer, generates
most of the muscle, blood and
connective tissues of the body
and placenta.
Endoderm: eventually most interior
of embryo, generates the
epithelial lining and associated
glands of the gut, lung, and
urogenital tracts.
Neural Induction:
In addition to patterning the forming mesoderm,
the primitive node also sets up the neural plate
•
•
Ectoderm exposed to
BMP-4 (from endoderm
and mesoderm below),
develops into skin
However, the node
secretes BMP-4
antagonists: (e.g.
noggin, chordin, &
follistatin) that allow a
region of the ectoderm
to develop into nerve
tissue.
Movie: neural induction
(click here for QuickTime version)
Neurulation: folding of the neural plate
1. Median hinge point forms (probably due
to signaling from notochord) –columnar
cells adopt triangular morphology (apical
actin constriction, like a purse string)
2. Lateral hinge point forms by a similar
mechanism (probably due to signaling
from nearby mesoderm).
3. As neural folds close, neural crest
delaminates and migrates away (more
on that later…)
4. Closure happens first in middle of the
tube and then zips rostrally and caudally.
Neurulation:
folding and closure
of the neural plate
• Folding and closure of the neural
tube occurs first in the cervical
region.
• The neural tube then “zips” up
toward the head and toward the
tail, leaving two openings which
are the anterior and posterior
neuropores.
• The anterior neuropore closes
around day 25.
• The posterior neuropore closes
around day 28.
Movie:
Movie:
Neurulation
Gastrulation to Somitogenesis
(click here for QuickTime version)
(click here for QuickTime version)
Errors in Neurulation:
Neural Tube Defects (NTDs)
1. Rachischisis: failure of neural tube folding.
2. Anencephaly: failure of the anterior
neuropore closure.
3. Spina bifida: failure of posterior neuropore
closure and/or vertebral development.
NTDs have many genetic and environmental causes, but
strongest correlation is folic acid deficiency.
– Best prevented by taking 400 ug folic acid (1000ug if family history of
NTDs) daily 3 months prior to conception and throughout pregnancy.
Rachischisis: failure of neurulation; i.e.,
the neural tube does not close
Rachischisis: spinal
cord
Cranioschisis: brain
Craniorachischisis:
brain & cord
Failure of neuropores to close can
cause neural tube defects
anterior neuropore: anencephaly
posterior neuropore: spina bifida
Anencephaly: failure of anterior
neuropore closure
Neural tube closure defects
A. Rachischisis, B. Spina bifida occulta, C. Meningocele,
D. Myelomeningocele
Spina bifida is often observed in the lumbar region
reflects to the approximate original location of the posterior neuropore
“Regression” of the spinal cord
The spinal cord and the vertebral column are
the same length up until the 3rd month.
As each vertebral body grows thicker, the
overall length of the vertebral column begins
to exceed that of the spinal cord such that , in
the adult the spinal cord terminates at L2 or 3
and the dural sac ends at about S2.
The tail end of the dural sac covering the spinal
cord and nerve roots remains attached at the
coccyx and becomes a long, thin strand called
the filum terminale.
Sometimes, the spinal cord can become
“tethered” or attached to the dural sac or
filum terminale; this pulls on the cord and can
obstruct flow of CSF thus causing swelling of
the ventricles of thebrain (hydrocephalus),
Hydrocephalus due to a tethered spinal cord
Disrupting flow of CSF causes it to accumulate within the
ventricles of the brain –increased pressure leads to
swelling of the entire cranium.
Neural Crest: the
th
“4
germ layer”
At the time of neurulation, cells at
the lateralmost edge of the neural
plate are exposed to a unique
combination of factors from the
adjacent skin, underlying mesoderm,
and from the rest of the neural plate
and are induced to form neural
crest.
The neural crest cells downregulate
cadherin expression and delmainte
from the neuroepithelium, i.e., they
transform from epithelial cells into
migratory mesenchymal cells that
contribute to forming MANY tissues
in the body.
Major Derivatives of the Neural Crest
Mesoderm is patterned in a cranial to caudal gradient
Axial mesoderm: passes through the
node and migrates along the midline
–forms the notochord
Paraxial mesoderm: passes just
caudal to the node and migrates
slightly laterally –forms cartilage,
skeletal muscle, and dermis
Lateral plate mesoderm: passes more
caudal and migrates more laterally –
forms circulatory system and body
cavity linings.
Extraembryonic mesoderm: passes
most caudal and migrates most
laterally –forms extraembryonic
membranes and associated
connective tissue & blood vessels.
Subdivision of the mesoderm
Chordamesoderm
– notochord
Paraxial mesoderm
– head mesenchyme
– somites
• sclerotome
• myotome
• dermatome
Intermediate mesoderm
– urogenital organs
Lateral plate mesoderm
– splanchnic (viscera)
– somatic (body wall)
– extraembryonic
Somitogenesis
Paraxial mesoderm form pairs of somitomeres (pre-somites)
Somitogenesis begins w/ 8th pair of somitomeres (pairs 1-7 don’t develop into somites)
Mesoderm (mesenchyme) is transformed back into epithelium –relies on Noggin
antagonism of BMP-4
Noggin
•
•
•
BMP
Separation of Somites
•
•
FGF signaling from the node drives proliferation; Retinoic acid from adjacent mesoderm drives
differentiation. Because the node is caudal to the forming somites, there is a head-to-tail
gradient of differentiation.
Proliferating cells express a ligand (called ephrin B1). As cells differentiate, they begin to
express an INCOMPATIBLE receptor (called eph A) that causes the differentiating cells to repel
the proliferating cells, thus pinching off and forming a new somite.
N-cad
(click here for QuickTime version)
Somites are balls of epithelial cells with a
few mesenchymal cells in the core
Epithelial somites then transform back into mesenchyme
• Signaling from ectoderm induces dermomyotome
• Signaling from notochord and neural tube induces sclerotome
Dermamyotome forms dermis and muscle
• BMP from ectoderm induces
dermatome the remaining dorsomedial
and ventrolateral cells become
myotome.
• Dorsomedial portion of dermomyotome
sees Shh from notochord and Wnt from
spinal cord and becomes muscle that
can’t migrate very far (epaxial muscles
of the back)
• Ventrolateral portion of dermomyotome
exposed to high levels of BMP from
lateral plate mesoderm and becomes
migratory muscle (goes into limbs also
“hypaxial” muscles of the lateral and
ventral body wall, e.g. “lats” and “abs”
The sclerotome develops into
vertebrae, ribs, and meninges
Dorsal sclerotome:
– Dorsal arch & spinous processes of
vertebrae*
Medial sclerotome:
– Meninges*
Central sclerotome:
– Pedicles & transverse processes of
vertebrae, proximal portions of ribs
Ventral sclerotome:
– Vertebral bodies and annulus
fibrosis of intervertebral disks
Lateral sclerotome:
– Distal portions of ribs
*failure of these associated w/ spina bifida
Somite (Paraxial mesoderm) forms:
1. Sclerotome
2. Dermamyotome
Sclerotome forms:
Meninges, vertebral bodies & ribs
Dermamyotome forms:
1. Dermis (from dermatome)
2. Muscles (from myotome)
(click here for QuickTime version)
The sclerotome breaks into two parts…
Anterior and posterior portions
of each sclerotome fuse to form
vertebral bodies. This offsets
the vertebral bodies and
segmental muscles.
i.e., the vertebrae (sclerotome) are out
of phase with muscle (myotome) to
form intervertebral joints. This allows
the contracting segmental muscles to
move the vertebral column laterally.
Anterior portion of one somite
fuses with the posterior portion
of the next somite; that way
The surrounding muscle bridges
sequential vertebral bodies.
(click here for QuickTime version)
Intermediate mesoderm develops
into the urogenital system
Lateral plate divides into somatic
and splanchnic mesoderm
Somatic mesoderm:
Lines body wall (somatic mesoderm
+ ectoderm = somatopleure)
Splanchnic mesoderm:
Covers endoderm (splanchnic mesoderm
+ endoderm = splanchnopleure)
Coelom = body cavity formed by lateral
folding of the embryo
Lateral plate mesoderm also generates
extraembryonic mesoderm of
amnion, yolk sac, and placenta.
Somatic (aka parietal) mesoderm stays with epidermis
Splanchnic (aka visceral) mesoderm stays with endoderm
Blood and blood vessels develop from
extraembryonic and lateral plate mesoderm
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•
•
•
Vasculogenesis: blood vessels arise de
novo from “hemangioblasts” that
develop into blood cells AND vascular
tubes
Angiogenesis: growth of new blood
vessels from existing ones
Vessels from extraembryonic
mesoderm go out to placenta and
eventually hook up with blood vessels
(and the heart) in the embryo that arise
from lateral plate mesoderm to
establish circulation.
2 major phases of hematopoiesis:
–
–
Embryonic (weeks 1-4) : blood cells
arise from yolk sac mesoderm
Definitive (week 4-term): blood cells
arise from lateral plate mesoderm in
the AGM (aorta-gonad-mesonephros
region) that go on to seed the spleen,
liver, and then bone marrow with
hematopoietic stem cells.
Segmentation of
the endoderm
Pharyngeal Gut
Oropharyngeal membrane
(stomodeum) to pharynx
Foregut
Trachea, esophagus, stomach,
duodenum, liver, and pancreas
Midgut
Small intestine, ascending colon,
proximal 2/3 of transverse colon
Hindgut
Distal 1/3 of transverse colon,
descending colon, rectum, cloacal
plate (proctodeum)
Segmentation of
the endoderm:
movie
(click here for QuickTime version)
(click here for QuickTime version)
Closure of the
body wall
Craniocaudal and
lateral folding draw
in the yolk sac (like a
pursestring) and
close off the body
wall except at the
umbilicus.
Simultaneous events:
Purse string-like closure
of the body wall
Growth of the amnion,
Regression of yolk sac.
Embryo grows into the amnion.
Yolk sac regresses.
(click here for QuickTime version)
Ectopia cordis:
failure of the thoracic
body wall to close
Gastroschisis:
failure of the
abdominal body wall
to close
Implantation & Placentation
The placenta is derived from the
trophoblast cells that further
differentiate and invade maternal
tissues
– Cytotrophoblast: stem cell
population
– Syncytiotrophoblast: invasive
fused cells (syncytium) derived
from cytotrophoblast
– Invasion process breaks into
maternal capillaries, trophoblastic
lacunae fill with maternal blood
(click here for QuickTime version)
The placenta allows for exchange (NOT mixing)
between maternal and fetal blood
• Early placental barrier
(weeks 1-12) has more
layers:
–
–
–
–
Syncytium
Cytotrophoblast
Embryonic conn. tissue
Endothelium
• Later placental barrier
(4th mo. – term) has
fewer layers:
early
later
– Syncytium
– Endothelium
Summary of fetal membranes
(and cavities)
•
•
•
Chorion: (part of the placenta) ring of
extraembryonic mesoderm from which
placental villi sprout
Chorionic cavity: aka extraembryonic coelom,
space between chorion and developing embryo
(gets smaller as the embryo and amnion
expand)
Amniotic cavity:
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–
•
•
space that is initially on the dorsal surface of the
embryo and then almost completely envelops
embryo with folding and closure of the body wall
bounded by the amniotic membrane and filled
with amniotic fluid
Yolk sac: space that is on the ventral surface of
the embryo and is drawn closed (like a
pursestring) with closure of the body wall.
Umbilical cord:
–
–
–
–
connection from the embryo to the
chorion/placenta
contains arteries conveying nutrient and oxygenpoor blood to the placenta and a single vein
conveying enriched blood back to the fetus
Also contains closed off yolk sac
During gut development intestinal loops herniate
into the umbilical cord and are eventually drawn
back into the fetus
Fertilization to term: the movie
(click here for QuickTime version)
Amniotic fluid
Typical volumes: 30 ml @ 10 wks; 450 ml @ 20 wks; 1l @ 37 wks
Produced by: amnion, maternal blood, fetal kidneys (5th month)
Taken up by fetal swallowing
Polyhydramnios: > 1500 ml (often result of gut or swallowing defect, also secondary to
maternal diabetes)
Oligohydramnios: < 400 ml failure to produce enough fluid (usu. Renal defects)
Amniotic Bands:
The amnion can ensnare parts of the fetus (usu. limbs)
and cause constriction or even amputation.
Often associated with oligohydramnios.
Twinning may result in sharing of placenta and/or fetal membranes
Shared placenta may result in twin transfusion syndrome where more blood goes to one fetus.
Dizygotic (aka “paternal”):
Monozygotic (aka “maternal”):