Third to Eighth Weeks The

Embryonic Period
 The Embryonic Period
• Refers to 3rd to 8th week of development
• It is the period of organogenesis
• the three germ layers, ectoderm, mesoderm, and
Endoderm, gives rise to a number of specific
tissues and organs
• By the end of the embryonic period, the main
organ systems have been established
• external body form recognizable by end of the 2nd
month
Derivatives of the Ectodermal Germ Layer

• Formation of the notochord and prechordal

mesoderm induces the overlying ectoderm to
thicken and form the neural plate
• Cells of the plate make up the neuroectoderm
• induction of the neuroectodermal cells is the
initial event in the process of Neurulation
• Induction of neural plate is caused by
upregulation of FGF and downregulation of
BMP4
• FGF downregulates BMP4 by increasing the
levels of chordin, noggin and follistatin
• In the presence of BMP4 ectoderm becomes
epidermis, and mesoderm forms intermediate
and lateral plate mesoderm
• If BMP4 is absent or inactivated, ectoderm
becomes neuralized
• noggin, chordin, and follistatin neuralize
ectoderm and cause mesoderm to become
notochord and paraxial mesoderm (dorsalizes
mesoderm) by inactivating BMP4
• noggin, chordin, and follistatin neuralize
ectoderm only in the forebrain and hind brain
• In the caudal neural plate structures (hind brain
and spinal this process is mediated by WNT3a
and FGF
• retinoic acid appears to play a role in organizing
the cranial-to-caudal axis
 Neurulation
• Is the process of formation of the neural tube
which represent the CNS in the developing
embryo
• Starts with induction of the neuroectodermal
cells in the neural plate and ends with the
formation of the neural tube
• With induction the elongated, slipper-shaped
neural plate gradually expands toward the
primitive streak
• The neural folds and neural groove are formed
at the end of the 3rd week
• The neural folds are the elevated lateral
margins of the neural plate while the
• Gradually, the neural folds approach each
other in the midline, where they fuse to
complete the formation of the neural tubes
• Fusion begins in the cervical region (fifth
somite) and proceeds cranially and caudally
• Before fusion is completed the neural tube
communicates with the amniotic cavity
– cranial neuropores at the cranial end
– caudal neuropores at the caudal end
• the cranial neuropore occurs on day 25 (18-
to 20-somite stage), whereas the posterior
neuropore closes at day 27 (25-somite stage)
• The completed neural tube represent the CNS
and is divided into three portions
I. narrow caudal portion
II. the spinal cord
III. a much broader cephalic portion
characterized by a number of dilations, the
brain vesicles
• By end of 3rd
week
• neural folds
form
• neural groove
form
• cells at the lateral border or crest of the
neuroectoderm of the neural fold are called
neural crest cells
• dissociate from their neighbors
• undergo an epithelial-to-mesenchymal trans-
ition
• leave the neuroectoderm by active migration and
displacement to enter the underlying mesoderm
• A,B → nueral crest formation
• Migrations starts after neural tube closes
• Pathways of migration of neural crest cells from
the trunk
• dorsal pathway
– dermis → enter ectoderm through holes in the
basal lamina → form melanocytes in the skin and
hair follicles
• ventral pathway
– anterior half of each somite → form sensory
ganglia, sympathetic and enteric neurons, Schwann
cells, and cells of the adrenal medulla
• neural crest cells from cranial neural folds
migrate before the neural tube closes and
contribute to
– craniofacial skeleton
– neurons for cranial ganglia
– glial cells
– Melanocytes
– other cell types
migratory paths of neural crest cells → head region
1–6, pharyngeal arches
V, VII, IX, and X, epibranchial placodes.
 TABLE 6.1 Neural Crest Derivatives

Neural Crest Derivatives

Connective tissue and bones of the face and skull
Cranial nerve ganglia
C cells of the thyroid gland
Conotruncal septum in the heart
Odontoblasts
Dermis in face and neck
Spinal (dorsal root) ganglia
Sympathetic chain and preaortic ganglia
Parasympathetic ganglia of the gastrointestinal tract
Adrenal medulla
Schwann cells
Glial cells
Meninges (forebrain)
Melanocytes
Smooth muscle cells to blood vessels of the face and forebrain
• In general, the ectodermal gives rise to organs
and structures that maintain contact with the
outside world:
– central nervous system
– peripheral nervous system
– the sensory epithelium of the ear, nose, and eye
– the epidermis, including the hair and nails. In
PLUS
• subcutaneous glands, the mammary glands,
the pituitary gland, and enamel of the teeth
Derivatives of the Mesodermal Germ
Layer

• Review of the components of the Mesodermal layer

 Paraxial Mesoderm
• 3rd week
• Paraxial mesoderm organized into Somitomeres
• Somitomeres first form in the cephalic region and
progress in cephalocaudally
• somitomere = mesodermal cells arranged in
concentric whorls around the center of the unit
• Somitomeres further organize into somites
starting in the occipital region and progressing
caudally
• 20th day of development → first pair of
somites arises in the occipital region → new
somites appear in craniocaudal sequence
• Rate of somite formation = three pairs per day
• Therefore 42 to 44 pairs are present at the
end of fifth week
– 4 occipital
– 8 cervical
– 12 thoracic
– 5 lumbar
– 5 sacral
– 8 to 10 coccygeal pairs
• The first occipital and the last five to seven
coccygeal somites disappear
• the remaining somites form the axial skeleton
• Somites appear with specified periodicity →
age of an embryo can be ccurately determined
during this early time period by counting
somites
 T Number of Somites Correlated to Approximate Age in Days

Approximate Age (days) Number of Somites

20 1–4
21 4–7
22 7–10

23 10–13

24 13–17

25 17–20

26 20–23

27 23–26

28 26–29

30 34–35
• Somites which are segmented are formed from
unsegmented presomitic (paraxial) mesoderm
• segment-patterning genes regulate somite
formation
• cyclic genes including (members of Notch and
WNT signaling pathways ) are expressed in the
paraxial mesoderm activate segment patterning
genes
• retinoic acid (RA) and FGF8 control the boundaries
for expression of segment patterning genes in the
paraxial mesoderm
– RA upregulates somite-patterning genes
– FGF8 represses RA and inhibit somite formation
• The ventral and medial walls of the somite are
formed by by a collection of cells known as
Sclerotome
• Sclerotome for mesenchyme and give rise to
– Tendons
– remainder surround the spinal cord and
notochord to form the vertebral column
• Cells that form the dorsolateral portion of the
somite also migrate as precursors of the limb
and body wall musculature
• cells at the dorsomedial form a new layer, the
myotome
• remaining dorsal epithelium forms the
dermatome
• Myotome + dermatome = dermatomyotome
– Each segmentally arranged myotome contributes to
muscles of the back
– dermatomes disperse to form the dermis and
subcutaneous tissue of the skin
• each myotome and dermatome retains its
innervation from its segment of origin, no
matter where the cells migrate
• Therefore each somite forms its own
– Sclerotome (the tendon cartilage and bone
component)
– Myotome (providing the segmental muscle
component)
– Dermatome, which forms the dermis of the back
– Each myotome and dermatome also has its own
segmental nerve component.
 Intermediate Mesoderm
• temporarily connects paraxial mesoderm with the lateral
plate
• differentiates into urogenital structures
• forms segmental cell clusters (future nephrotomes), in
cervical and thoracic region
• unsegmented mass of tissue, the nephrogenic cord
forms more caudally
• Excretory units of the urinary system and the gonads
develop from partly segmented, partly unsegmented
intermediate mesoderm
 Lateral Plate Mesoderm
• Somatic or parietal lateral mesoderm with
contribution from overlying ectoderm forms
– lateral and ventral body wall
– Parietal peritoneal, pleural and pericardial membranes
• Splanchnic of visceral lateral plate mesoderm and
embryonic endoderm will form
– the wall of the gut
– Visceral peritoneal, pleural and pericardial membranes
 Blood and Blood Vessels
• Blood vessels form in two ways
I. Vasculogenesis vessels → arise from blood
islands that form early in the 3rd week in
– Mesoderm surrounding the yolk sac
– Lateral plate mesoderm
II. Angiogenesis → new blood vessels sprouting
from existing vessels
• Mesodermal cell forming blood island cells are
induced to form hemangioblasts
• Hemangioblasts are the common precussors of
blood vessels and blood
• Hemangioblasts in the center of blood islands
form hematopoietic stem cells, the precursors
of all blood cells
• peripheral hemangioblasts differentiate into
angioblasts, the precursors to blood vessels
– Angioblasts endothelial cells
– Endothelial cells then coalesce under the
VEGF
influence VEGF to form primitive blood vessels
• vasculogenesis establishes a primary vascular
bed
• vasculogenesis establishes a primary vascular
bed including
– dorsal aorta
– cardinal veins
• angiogenesis adds the sprouting of new vessels
regulated by VEGF
• PDGF and TGFb regulate maturation and
modeling of the vasculature
• Specification of arteries, veins, and the lymphatic
system occurs soon after angioblast induction
Extraembryonic blood vessel formation in the villi,chorion,
connecting stalk, and wall of the yolk sac
• the first blood cells arise in the blood islands of
the yolk sac
– this population is transitory
• The definitive hematopoietic stem cells arise from
mesoderm surrounding the aorta in a site called
the aorta-gonad-mesonephros region (AGM).
• These cells will colonize the liver, which becomes
the major hematopoietic organ of the fetus
• Later, stem cells from the liver will colonize the
bone marrow, the definitive blood-forming tissue
 Clinical Application

• Capillary hemangiomas
– Collection of capillary blood vessels
– Most common tumor of infancy
– Affects 10% of newborns
– Can occur in any location
– But most common in the head and nect region
– Localized or diffuse
– Complications → bleeding, ulceration, scarring
and airway obstruction
Derivatives of the Endodermal Germ Layer

• The endoderm covers the ventral surface of the

embryo and forms the roof of the yolk sac
• Mainly give rise to the gastrointestinal tract
• Anterior part →Foregut
• in the tail region → Hindgut
• The part between foregut and hindgut → Midgut
– temporarily communicates with the yolk sac via a broad
stalk, the Vitelline duct
– becomes narrow and much longer with growth of the
embryo
• Development and growth of the brain vesicles
affect the embryonic disc in two ways
I. Embryonic disc bulges into the amniotic
cavity
II. Embryonic disc folds cephalocaudally
forming the head and tail folds
derivatives of the endodermal germ layer
• The primitive gut is bounded at its cephalic and
caudal ends by ectodermal-endodermal
membranes
• The cephalic membrane is called the
Buccopharyngeal membrane
– Ruptures during the 4th week, establishing a connection
between the amniotic cavity and the primitive gut
• The caudal membrane is called the cloacal
membrane
– breaks down in the 7th week to create the opening for
the anus
• Rapid growth of the somites result in lateral folding
of the embryo → round appearance
• At the same time the ventral body wall of the
embryo is established, except for a small part in
region where the yolk sac duct and connecting
stalk are attached
• While the foregut and hindgut are established, the
midgut remains in communication with the yolk
sac.
• Initially this connection is wide
• gradually becomes long and narrow to form the
Vitelline duct
• Folding also result in partial incorporation of
the allantois into the body of the embryo
• This incorporated allantois forms the Cloaca
• The distal portion of the allantois remains in
the connecting stalk
• By the fifth week, the yolk sac duct, allantois,
and umbilical vessels are restricted to the
region of the umbilical ring
• Fate of the yolk sac in humans
• It is a vestigial structure in humans
• in all probability has a nutritive role only in
early stages of development
• In the second month of development, it lies in
the chorionic cavity
 Summary of derivatives of endoderm

• initially forms the epithelial lining of the

primitive gut and the intraembryonic portions
of the allantois and vitelline duct
• During further development, it gives rise
– the epithelial lining of the respiratory tract
– the Parenchyma of the thyroid, parathyroids, liver,
and pancreas
– the reticular stroma of the tonsils and thymus
– the epithelial lining of the urinary bladder and
urethra
– the epithelial lining of the tympanic cavity and
auditory tube
 External Appearance During the Second
Month
• At the end of the 4th week the embryo has
approximately 28 somites
• the main external features are the somites
and pharyngeal arches
• somites are used to determine the age of the
embryo.
• counting somites becomes difficult during the
second month of development
• Then the age of the embryo is indicated as the
crown-rump length (CRL), expressed in
millimeters
– CRL is the distance from the vertex of the skull to
the midpoint between the apices of the buttocks
• The external features in the embryo in the
second month include :
• increase in head size
• formation of the limbs, face, ears, nose, and eyes
• beginning of the 5th week → forelimbs and
hindlimbs appear as paddle-shaped buds
• The forelimbs are located dorsal to the
pericardial swelling at the level of the fourth
cervical to the first thoracic somites
– this explains their innervation by the brachial plexus
• The hindlimb buds appear slightly later just
caudal to attachment of the umbilical stalk at
the level of the lumbar and upper sacral
somites
• fingers and toes are begin to form
 Clinical Applications

• Birth Defects
• Most major organs and organ systems are formed
during the third to eighth weeks
• called the period of Organogenesis
• sensitive to insult from genetic and
environmental influences
• Therefore most gross structural birth defects are
induced during the embryonic period
• third and fourth weeks are particularly vulnerable
CRL Approximate Age in WEEKS
5–8 5

10–14 6

17–22 7

28–30 8
 SUMMARY
• The embryonic period (3rd to the 8th weeks) of
development is the period of organogenesis
• major features of body form are established
• The ectodermal germ layer gives rise to the
organs and structures that maintain contact
with the outside world:
• central nervous system
• peripheral nervous system
• sensory epithelium of ear, nose, and eye
• skin, including hair and nails
• pituitary, mammary, and sweat glands
• enamel of the teeth
• mesodermal germ layer → paraxial, intermediate, and
lateral plate mesoderm
• Paraxial mesoderm → Somitomeres
• Somitomeres → mesenchyme of the head and
organize into Somites in occipital and caudal segments
• Somites → Myotome (muscle tissue), Sclerotome
(cartilage and bone), and Dermatome (subcutaneous
tissue of the skin), which are all supporting tissues of
the body
• Signals for somite differentiation are derived from
surrounding structures, including the notochord,
neural tube, and epidermis.
•  
• The endodermal germ layer provides
• the epithelial lining of the gastrointestinal tract,
respiratory tract, and urinary bladder
• forms the Parenchyma of the thyroid,
parathyroids, liver, and pancreas
• epithelial lining of the tympanic cavity and
auditory tube originate in the endodermal germ
layer 

• Craniocaudal patterning of the embryonic axis is

controlled by homeobox genes
• formation of organ systems and rapid growth
of the CNS → initial flat embryonic disc begins
to fold cephalocaudally, establishing the head
and tail folds
• The disc also folds transversely (lateral folds),
establishing the rounded body form
• Connection with the yolk sac is maintained
through the vitelline duct
• Connection with the placenta is maintained
through the umbilical cord, respectively