BY MUNEEB HASAN KHAN
THIRD WEEK OF DEVELOPMENT
1.
Gastrulation:
·
The formative morphogenetic process in which the 3 germ layers
(primordia of all embryonic tissues) and axial orientation of embryo are
established.
·
Begins with proliferation and migration of epiblastic cells to
median plane of embryonic disc causing appearance of a thickened band i.e. primitive
streak (under influence of NODAL) on dorsal epiblastic surface at caudal end
(clearly visible by day 15-16). It elongates by addition of cells caudally and
its cranial end proliferates to form a slightly elevated primitive node.
·
Concurrently, epiblastic cells migrate towards the streak (due to
downregulation of epiblastic Cadherin by FGF-8 released by streak cells) and invaginate
deep to it, causing primitive groove to appear in the streak which is
continuous with primitive pit in the node.
·
The invagination of epiblastic cells from middle & caudal parts
of streak produces mesenchyme (loose embryonic C.T.) from which are derived all
3 germ layers in form of trilaminar disc:
i.
Ectoderm – formed by remaining epiblastic cells after other layers are
formed.
ii.
Mesoblast
– undifferentiated mesoderm formed as
a new layer between endoderm & ectoderm that later on differentiates into 3
different types of mesoderm.
iii.
Endoderm
– formed by displacement of
hypoblastic cells by invaginating epiblastic cells.
·
Invagination from cranial part of primitive node produces some
special derivatives:
i.
Primordial
Germ Cells (PGCs) –formed in 2nd
week, these invaginate and migrate to endodermal wall of yolk sac, and later to
gonadal regions.
ii.
Prenotochordal
Cells – invaginate from cranial part of
primitive node and form notochord.
iii.
Prechordal
Plate -a compact mass of cells between
oropharyngeal membrane and tip of notochord that forms from the earliest cells
that ingress through primitive node & migrate cranially. It has 2
functions:
o Serves as inductor of cranial structure like forebrain
& eyes.
o Contributes endoderm for oropharyngeal membrane.
o Prechordal
mesoderm is a mesenchymal population of
neural crest origin rostral to notochord.
o Left-Right body axis is established
by molecular control in following manner: o FGF8 secreted by streak cells induces expression of NODAL.
o NODAL expression is limited to left side by serotonin
(5HT), and prevented from crossing over
to right side by midline genes e.g. SHH, LEFTY1 & ZIC3 (disruption of 5HT activity can result in situs inversus and other laterality-related defects).
o
NODAL
initiates a signaling cascade that
causes upregulation of PITX2, which is master gene for establishing left-sidedness (ectopic
expression of PITX2 results in laterality defects).
2.
Formation
of Notochord:
·
Prenotochordal
cells invaginate from cranial end of
primitive node & form a median cellular cord i.e. notochordal process that elongates in a caudo-cranial fashion until it reaches
prechordal plate.
·
The indentation of primitive pit elongates and extends into the process to form notochordal canal, converting the notochordal process into a cellular tube.
·
By day 18, floor of the notochordal process fuses with underlying
embryonic endoderm and both of them degenerate, with following results:
i. The notochordal canal communicates with umbilical
vesicle – first through small openings in
the floor of the canal, that gradually become confluent until the entire floor
disappears. ii. The remains of notochordal process form a flattened, grooved notochordal plate.
iii. A transient connection is established between amniotic and umbilical
vesicle cavities, through the Neurenteric canal present in proximal part of the canal. It’s obliterated when
notochord development is complete.
·
Notochordal plate cells proliferate and undergo infoldings,
resulting in formation of definitive notochord that proceeds in a cranio-caudal
fashion.
·
Notochord then detaches from endoderm and the latter again becomes
a continuous layer.
·
Notochord disappears when bodies of vertebrae form (in 4th week),
but persists as nucleus pulposus of the intervertebral discs.
·
It does the following given functions:
i.
Gives rigidity to embryo and defines its longitudinal axis
ii.
Provides inductive signals for development of CNS & axial
musculoskeletal structures
3.
Organization
of Intraembryonic Mesoderm:
·
Derived from invagination of cells from
a)
Caudal part of primitive node
b)
Major part of primitive streak
c)
Possibly from proliferation of cells from notochordal process
·
Initially exists as undifferentiated mesoblast between ectoderm and endoderm that differentiates into different
types of mesoderm as it expands:
i.
Cranially
– mesodermal cells migrate on each side of notochordal process & around
prechordal plate and meet
cranially to form cardiogenic
mesoderm (where heart primordium develops at
end of 3rd week).
ii.
Bilaterally – on both left & right sides, mesoblast proliferates until it
reaches margins of embryonic disc and here it becomes continuous with extraembryonic mesoderm. The remaining intraembryonic mesoderm differentiates into 3
regions from medial to lateral:
1)
Paraxial
– thick longitudinal column
immediately lateral to notochord.
2)
Intermediate
– thinner column b/w paraxial and
lateral mesoderm.
3)
Lateral
Plate - thin, sheet-like mesoderm whose
right and left parts are joined by cardiogenic
mesoderm, and is continuous with extraembryonic mesoderm.
·
By middle of 3rd week, intraembryonic mesoderm is
present everywhere except:
i. Oropharyngeal
membrane – region of tightly adherent ectoderm
+ endoderm cranially.
ii. Cloacal
membrane – same as above but located caudally. iii. Notochord
– in median plane cranial to primitive
node.
4.
Formation
of Intraembryonic Coelom:
·
By 18th day, coelomic spaces appear in cardiogenic mesoderm & lateral
plate mesoderm of both sides that eventually coalesce to form U-shaped cavity
i.e. intraembryonic coelom which is continuous with extraembryonic coelom on
either side of embryo.
·
This splits the lateral plate mesoderm into 2 layers:
a)
Somatopleure
–located beneath ectoderm and continuous with extraembryonic mesoderm covering amnion.
b)
Splanchnopleure
–located adjacent to endoderm& continuous with extraembryonic mesoderm covering umbilical vesicle.
·
The 3 body cavities are derived from the coelom as:
Ø Cranial-most part lies in
cardiogenic plate and forms pericardial
cavity; cranial to it, a mass of mesoderm
remains unsplit and forms septum transversum.
Ø Right and left limbs partially merge
in later development and form the paired pleural
cavities and single peritoneal cavity.
5.
Neurulation:
·
Process involved in formation of neural plate and neural folds followed
by closure of the latter to form neural tube.
·
Begins in middle of 3rd week when developing notochord & prechordal
mesoderm induce overlying ectoderm (called neuroectoderm) to become thickened
in midline as neural plate (that is broader at cranial end but tapers at caudal
end).
o At first its
length correlates to that of underlying notochord, but eventually extends way
beyond it i.e.
a)
As far cranially as oropharyngeal
membrane
b)
As well as caudally following recession of primitive node &
streak that occurs due to differential growth of embryonic disc.
·
On ~day 18, neural plate invaginates along its central axis to form
longitudinal median neural groove, flanked by raised margins i.e. neural folds
(that are particularly large at cranial end and are first sign of brain
development).
·
Starting from end of 3rd week and completing in 4th week, the folds
begin to move towards each other in midline (beginning in cervical region and
moving cranially and caudally) and fuse to form neural tube.
·
This also brings the opposing margins of surface ectoderm
together, so they fuse and neural tube eventually separates from surface
ectoderm.
·
Until fusion is complete, neural tube communicates with amniotic
cavity at either end through:
i.
Cranial
neuropore–closes by day 25.
ii.
Caudal
neuropore–closes by day 28 and completes
process of neurulation.
6.
Neural
Crest Formation:
·
It is a population of cells located at inner lateral margin of each
neural fold.
·
When neural tube closes & detaches from surface ectoderm, these
cells undergo epithelial-to mesenchymal transition and form a flattened
irregular mass of cells i.e. neural crest between neural tube & overlying
surface ectoderm.
·
The crest separates into right and left parts and migrates to dorsolateral
aspects of neural tube, from where they undergo widespread dissemination along
predefined pathways.
·
Major derivatives of neural crest cells are:
|
System |
Derivative |
|
Nervous |
1.
Spinal (dorsal root) ganglia 2.
Parasympathetic ganglia of GIT 3.
Sympathetic chain + preaortic ganglia 4.
Ganglia of Cranial Nerves V, VII, IX, X 5.
Leptomeninges (dura + pia mater) 6.
Schwann cells & neurolemmal sheath of peripheral
nerves 7.
Glial cells |
|
Glands |
1.
Adrenal medulla 2.
C-cells of thyroid gland |
|
Skin |
1.
Melanocytes 2.
Dermis of face and neck |
|
Cardiovascular |
1.
Conotruncal septum in heart 2.
Smooth muscle in blood vessels of face &
forebrain |
|
Connective
Tissue |
1.
Bones & C.T. of face and neck 2.
Cartilages of pharyngeal arches 3.
Odontoblasts |
7.
Formation
of Somites:
·
Cube-shaped blocks of condensed paraxial mesoderm that appear in
pairs on either side of neural tube during the somite
period of development (i.e. days 20 – 30; end of 3rd week till beginning of 5th
week).
·
Appearance is regulated by a molecular
clock established by cyclic expression of
NOTCH &WNT pathways in presomitic mesoderm that produce somites at the rate of
3 to 4 per day – a useful estimate for embryonic age during the 4th&
5th weeks.
ð Around 44 pairs are formed in total
(4 occipital, 8 cervical, 12 thoracic, 5 lumbar, 5 sacral, 8-10 coccygeal).
ð First occipital and last 5-7
coccygeal degenerate, giving final count of 38
pairs.
ð The first somite appears in occipital region of embryo, just caudal to the otic
placode.
ð Formation of new somites proceeds
caudally.
·
Somites form & differentiate as follows:
o Soon after its
formation, paraxial mesoderm becomes segmented into disc-like whorls of cells called somitomeres, extending from cranial to caudal regions.
ð Segmentation proceeds in a
craniocaudal fashion.
ð First seven (cranial) pairs
degenerate and blend with mesenchyme of head & neck, & thus never
become somites.
·
Remaining somitomeres form the nascent somites as a loose ball of
mesenchymal cells that undergo a process of epithelization and arrange in a
donut-shape around a central cavity (i.e.
·
somitocoele).
·
Different portions of somite become mesenchymal again and
differentiate into 3 parts:
|
PART |
DISTRIBUTION
|
DERIVATIVE
|
|
Sclerotome |
Ventromedial part (migrates around
notochord & neural tube) |
Axial skeleton (bone,
tendon, cartilage) |
|
Dermatome |
Dorsolateral part (central portion) |
Dermis of back |
|
Myotome |
Dorsolateral part (Dorsomedial ‘DML’ & ventrolateral ‘VLL’
tips) |
Epaxial + hypaxial
skeletal muscles |
·
Each dermomyotome receives its own segmental nerve supply from
spinal cord.
Ø Motor axons are guided to myoblasts in somites and migrate along with them.
Ø Sensory fibres go to dermatome for skin of back.
8.
Appearance
of Allantois:
·
Appears on day 16 as a diverticulum from caudal wall of umbilical
vesicle (subsequent to formation of cloacal
membrane) and extends into connecting stalk.
·
Remains rudimentary in humans (stores renal waste in lower
vertebrates).
·
Extraembryonic part degenerates in 2nd month. Proximal
part persists during development as urachus, replaced in adult as median
umbilical ligament (extending from
bladder to umbilicus).
·
Allantoic mesoderm expands beyond chorion and contributes to
formation of blood (in 3rd – 5th weeks) and umbilical arteries (but not umbilical veins) that regress in adulthood to form medial umbilical ligament.
9.
Formation
of Primitive Vascular System:
·
Since diffusion is no longer sufficient to nourish the embryo by
end of 2nd week, a primitive cardiovascular system starts developing
at start of 3rd week and is completed by its end.
·
Extraembryonic
mesoderm, connecting stalk, chorion are
first to develop vessels. Intraembryonic
vessels form 2 days later.
·
Mesodermal cells are specialized to form haemangioblasts that aggregate to form blood islands associated with:
a)
Wall of yolk sac
b)
Endothelial
cords within embryo.
·
Soon the islands acquire cavities by confluence of intercellular
clefts. Then they form vessels by 2 methods:
1.
Vasculogenesis
– (de novo development of new
vessels); Angioblasts flatten and form endothelial
cells that arrange around the cavity to
form endothelium. Many such cavities fuse to form a vascular network.
2.
Angiogenesis
– (branching of existing vessels);
additional vessels sprout into adjacent areas by endothelial budding and fuse
with other vessels.
·
Muscular
and connective tissue layers are formed by
surrounding mesenchymal cells.
10. Formation of
Blood Cells:
·
Earliest blood cells arise from haemoangiogenic
epithelium of blood
islands and vessels in following regions, but this population is transitory:
1)
Umbilical vesicle
2)
Allantois
3)
Specialized sites along dorsal aorta
4)
Directly from hemoangiopoetic
cells
·
Proper hematogenesis begins starting 5th week; it comprises definitive hematopoetic stem cells derived from mesoderm in a site near kidney called aorta-gonad-mesonephron (AGM) region, and they colonize different regions during embryonic life: 1) First along Aorta.
2)
Liver (by 9th week)
3)
Spleen
(by 12th week)
4)
Bone
marrow (by 28th week), which is
definitive blood-forming tissue of adult.
11. Formation of
Primitive Heart& Great Vessels:
·
Develop from mesenchyme in cardiogenic
plate.
·
In 3rd week, paired, longitudinal, endothelium-lined endocardial heart tubes form that fuse to form primordial
heart tube that connects with intraembryonic and umbilical
vessels.
·
On 21st/22nd day, primitive
cardiovascular system becomes
functional with initiation of heartbeat and circulation of
blood.
Development
of Secondary & Tertiary Chorionic Villi:
·
The primary villi begin to branch soon after their formation.
·
Soon they acquire a mesenchymal
core to become secondary chorionic villi that cover entire surface of chorionic sac.
·
The mesenchyme develops blood vessels to convert them into tertiary chorionic villi.
Ø Capillaries in the villi form arteriocapillary networks of placenta.
Ø These are connected to embryonic
heart and intraembryonic circulation via umbilical
vessels
(that form in
connecting stalk and extraembryonic mesoderm)
Ø Blood begins to flow at end of 3rd
week following formation of primitive heart.
·
Cytotrophoblast of villi grows & extends through the
syncytiotrophoblast, eventually forming a cytotrophoblastic
shell that surrounds chorionic sac and
anchors it to endometrium.
·
2 types of villi are seen:
1.
Stem
villi - attach fetal chorionic plate to
maternal decidual plate via the cytotrophoblastic shell.
2.
Branch
villi – grow from sides of the stem villi
and are bathed in maternal blood in intervillous spaces.
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