This document summarizes the embryonic period from 4-8 weeks of development. During this time, the three germ layers differentiate to form major organ systems. The ectoderm forms the central nervous system, skin, and sensory organs. The mesoderm forms muscles, skeleton, cardiovascular and lymphatic systems. The endoderm forms the lining of the digestive tract and its derivatives. Key events include somite formation, neurulation, and the development of the neural crest cells which contribute to many tissues. The molecular regulation of blood vessel formation is also discussed.

1. EMBRYONIC PERIOD
DR. SUNDIP CHARMODE
ASSOCIATE PROFESSOR
DEPARTMENT OF ANATOMY
AIIMS RAJKOT

2. INTRODUCTION
• This period begins from the beginning of 4th week to the end of
8th week.
• Ectodermal layer – protection
• Endodermal layer - nutrition
• Mesodermal layer - skeletal tissue, muscles and blood-vascular
system

3. INTRODUCTION
• By the end of the embryonic period, the main organ systems
have been established, rendering the major features of the
external body form recognizable by the end of the second
month.
• The third to eighth weeks are also cited as the time when the
majority of birth defects are induced; prior to this time, any
insult to the embryo results in its death and spontaneous
abortion.

4. INTRODUCTION
• Fourth week: sees individual differentiation of three germ
layers and formation of the folds of embryo.
• During Second month: all major organs and tissues are laid
down from the germ layers and external appearance of embryo
is recognizable.

5. DIFFERENTIATION IN ECTODERMAL LAYER
• Fourth week: appearance of series of mesodermal somites on
each side of middle line. (most important feature)
• Appear between 20th and 30th day of development
• Age of embryo - Pre-somite, Somite and Post-somite periods
• Crown to rump length (C.R.)
• Crown to heel length (C.H.)

7. DIFFERENTIATION IN ECTODERMAL LAYER
• Neuroectodermal cells thicken and formation of medullary or neural
plate – Pre-somite period
• Neural plate forms neural groove – Somite period
• Neural crest cells
• Neural groove extends from Hensen’s pole to buccopharyngeal
membrane in the middle line
• Conversion of neural plate into neural tube – ‘Neurulation’

8. DIFFERENTIATION IN ECTODERMAL LAYER
• Cephalic part of neural tube is enlarged to form three successive
vesicles- fore brain, mid brain and hindbrain, separated by two
circular constrictions.

10. 16 days 18 days

11. 19 days, 20 days, 22 days and 23 days

12. DIFFERENTIATION IN ECTODERMAL LAYER
• The ectodermal germ layer gives rise to the organs and structures that
maintain contact with the outside world:
1. Central nervous system
2. Peripheral nervous system
3. Sensory epithelium of ear, nose, and eye
4. Skin, including hair and nails
5. Pituitary, mammary, and sweat glands and enamel of the teeth

13. DIFFERENTIATION IN ECTODERMAL LAYER
• Induction of the neural plate is regulated by inactivation of the
growth factor BMP4. In the cranial region, inactivation is
caused by noggin, chordin, and follistatin secreted by the node,
notochord, and prechordal mesoderm.
• Inactivation of BMP4 in the hindbrain and spinal cord regions is
effected by WNT3a and FGF.

14. DIFFERENTIATION IN ECTODERMAL LAYER
• In the absence of inactivation, BMP4 causes ectoderm to
become epidermis and mesoderm to ventralize to form
intermediate and lateral plate mesoderm.

15. DIFFERENTIATION IN ECTODERMAL LAYER
1. The entire central and peripheral nervous system, including cranial, spinal
and autonomic ganglia.
2. Surface ectoderm forms outer protective covering of the embryo and helps
in development of epidermis, hair, nails, sebaceous and sweat glands.
3. Epithelial lining of cheek and gums, enamel of teeth, roof of the mouth,
nasal cavity and the paranasal sinuses, salivary glands, lower part of the
anal canal and terminal part of urethra.
4. Anterior and posterior lobes of hypophysis cerebri, chromaffin organs.

16. DIFFERENTIATION IN ECTODERMAL LAYER
5. External acoustic meatus, outer lining of tympanic membrane and
membrane labyrinth of the internal ear.
6. Corneal epithelium, conjunctiva, lacrimal gland, nasolacrimal duct, lens
and retina.
7. Muscles of iris, and arrectores pilorum of the skin.

17. NEURAL CREST CELLS
• As the neural folds elevate and fuse, cells at the lateral border or crest of
the neuroectoderm begin to dissociate from their neighbours.
• This cell population, the neural crest cells, undergoes an epithelial-to-
mesenchymal transition as it leaves the neuroectoderm by active migration
and displacement to enter the underlying mesoderm.
• Crest cells from the trunk region leave the neuroectoderm after closure of
the neural tube and migrate along one of two pathways:

19. NEURAL CREST CELLS
• (1) a dorsal pathway through the dermis, where they will enter the ectoderm
through holes in the basal lamina to form melanocytes in the skin and hair
follicles, and
• (2) a ventral pathway through the anterior half of each somite to become sensory
ganglia, sympathetic and enteric neurons, Schwann cells, and cells of the adrenal
medulla.
• NCC also form and migrate from cranial neural folds, leaving the neural tube
before closure in this region. These cells contribute to the craniofacial skeleton as
well as neurons for cranial ganglia, glial cells, melanocytes, and other cell types.

20. NEURAL CREST CELLS
• NCC are so fundamentally important and contribute to so many
organs and tissues that they are sometimes referred to as the fourth
germ layer.
• They are also involved in at least one-third of all birth defects and
many cancers, such as melanomas, neuroblastomas, and others.

21. NEURAL CREST DERIVATIVES
1. Connective tissue and bones
of the face and skull
2. Cranial nerve ganglia
3. C cells of the thyroid gland
4. Conotruncal septum in the
heart
5. Odontoblasts
6. Dermis in face and neck
7. Spinal [dorsal root] ganglia
8. Sympathetic chain and
preaortic ganglia
9. Parasympathetic ganglia of
the gastrointestinal tract
10. Adrenal medulla
11. Schwann cells
12. Glial cells
13. Meninges [forebrain]
14. Melanocytes
15. Smooth muscle cells to
blood vessels of the face and
forebrain

22. CLINICAL CORRELATES
• Neural tube defects [NTDs] result when neural tube closure fails
to occur.
• If the neural tube fails to close in the cranial region, then most
of the brain fails to form, and the defect is called anencephaly.
• If closure fails anywhere from the cervical region caudally, then
the defect is called spina bifida. The most common site is in the
lumbosacral region.

23. CLINICAL CORRELATES
• Anencephaly is a lethal defect, and most of these cases are
diagnosed prenatally and the pregnancies terminated.
• Children with spina bifida lose a degree of neurological function
based on the spinal cord level of the lesion and its severity.
• Various genetic and environmental factors apparently account
for the variability.

24. CLINICAL CORRELATES
• Mutations in the VANGL genes have been identified and associated
with familial cases of these defects.
• The VANGL genes are part of the planar cell polarity pathway that
regulates convergent extension, the process that lengthens the neural
tube and is necessary for normal closure to occur.
• It is estimated that 50% to 70% of NTDs can be prevented if women
take 400 pg of folic acid daily [the dose present in most
multivitamins] beginning 3 months prior to conception and
continuing throughout pregnancy.

26. DIFFERENTIATION IN MESODERMAL LAYER
1. All connective tissue and sclerous tissue
2. Teeth with the exception of enamel
3. All muscles of the body, except the muscles of the iris and arrectores
pilorum of the skin
4. Cardiovascular and lymphatic system
5. Kidneys and gonads of urogenital system
6. Suprarenal cortex
7. Mesodermal lining of pericardial, pleural and peritoneal cavities.

27. BLOOD AND BLOOD VESSELS
• Blood cells and blood vessels also arise from mesoderm.
• Blood vessels form in two ways: Vasculogenesis, whereby vessels arise
from blood islands, and Angiogenesis, which entails sprouting from
existing vessels.
• The first blood islands appear in mesoderm surrounding the wall of the
yolk sac at 3 weeks of development and slightly later in lateral plate
mesoderm and other regions. Fig.
• These islands arise from mesoderm cells that are induced to form
hemangioblasts, a common precursor for vessel and blood cell formation.

28. Mesoderm cells – FGF-2 Hemangioblasts (VEGF) Tube formation

30. • FIGURE 6.15
:Extraembryonic blood
vessel formation in the villi,
chorion, connecting stalk,
and wall of the yolk sac in a
pre-somite embryo of
approximately 19 days.

31. BLOOD AND BLOOD VESSELS
• Although the first blood cells arise in blood islands in the wall of the
yolk sac, this population is transitory.
• The definitive hematopoietic stem cells are derived from mesoderm
surrounding the aorta in a site near the developing mesonephric
kidney called the aorta-gonad-mesonephros region (AGM).
• These cells colonize the liver, which becomes the major
hematopoietic organ of the embryo and fetus from approximately the
second to seventh months of development.

32. BLOOD AND BLOOD VESSELS
• Stem cells from the liver colonize the bone marrow, the
definitive blood-forming tissue, in the seventh month of
gestation; thereafter, the liver loses its blood-forming function.

33. MOLECULAR REGULATION OF BLOOD
VESSEL FORMATION
• FGF2 induces blood island development from competent mesoderm cells that
form hemangioblasts.
• Hemangioblasts are directed to form blood cells and vessels by vascular
endothelial growth factor (VEGF), which is secreted by surrounding mesoderm
cells. The signal to express VEGF may involve HOXBS, which upregulates the
VEGF receptor FLKl (Fig. 6.14).
• Hemangioblasts in the center of blood islands form hematopoietic stem cells,
the precursors of all blood cells, whereas peripheral hemangioblasts
differentiate into angioblasts, the precursors to blood vessels.

34. MOLECULAR REGULATION OF BLOOD
VESSEL FORMATION
• These angioblasts proliferate and are eventually induced to form
endothelial cells by VEGF secreted by surrounding mesoderm cells. This
same factor then regulates coalescence of these endothelial cells into the
first primitive blood vessels.
• Once the process of vasculogenesis establishes a primary vascular bed,
which includes the dorsal aorta and cardinal veins, additional vasculature is
added by angiogenesis, the sprouting of new vessels.
• This process is also mediated by VEGF, which stimulates proliferation of
endothelial cells at points where new vessels are to be formed.

35. MOLECULAR REGULATION OF BLOOD
VESSEL FORMATION
• Maturation and modelling of the vasculature are regulated by other
growth factors, including platelet-derived growth factor (PDGF) and
TGF-B, until the adult pattern is established.
• Specification of arteries, veins, and the lymphatic system occurs
soon after angioblast induction.

36. CAPILLARY HEMANGIOMAS
• Capillary haemangiomas are abnormally dense collections of
capillary blood vessels that form the most common tumors of
infancy, occurring in approximately 10% of all births.
• They may occur anywhere but are often associated with
craniofacial structures.
• Facial lesions may be focal or diffuse, with diffuse lesions
causing more secondary complications, including ulcerations,
scarring, and airway obstruction [mandibular hemangiomas].

37. CAPILLARY
HEMANGIOMAS
• Insulin—like growth factor 2
is highly expressed in the
lesions and may be one factor
promoting abnormal vessel
growth.
• Whether or not VEGF plays a
role has not been determined.

38. DIFFERENTIATION IN ENDODERMAL LAYER
• From the foregut:
1. Epithelial lining of pharynx, esophagus, stomach, duodenum up to
ampulla of Vater, and the mucous membrane of tongue.
2. Epithelial lining of respiratory system, auditory tube and tympanic cavity
3. Parenchyma of the tonsil, thyroid, parathyroid, thymus, liver and
pancreas.

39. DIFFERENTIATION IN ENDODERMAL LAYER
• From the midgut:
1. Mucous membrane of alimentary canal extending from the duodenum
distal to the ampulla of Vater up to the junction of right 2/3rd and left
1/3rd of transverse colon.
2. Meckel's diverticulum, when exists, is derived from the persistent
proximal part of vitello-intestinal duct.

40. DIFFERENTIATION IN ENDODERMAL LAYER
• From the hindgut:
1. Mucous membrane of digestive tube extending from left third of the
transverse colon up to muco-cutaneous junction of anal canal (pectinate
line).
2. Most of the mucous membrane of urinary bladder and urethra,
parenchyma of the prostate, bulbo-urethral or greater vestibular glands.
3. Epithelial lining of vagina
4. Probably, primitive sex cells are derived from dorsal wall of the hind gut.

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