Week 3 of Embryonic Development

Trilaminar Germ Disk Embryo Formation and Gastrulation

week 3 is a period of rapid development of the conceptus coinciding with the first missed menstrual period.

By days 15-16, the embryo is 1.5 mm long, and one clearly sees the primitive streak, Hensen’s node, and the notochordal process- All morphologic indications characteristic of gastrulation. The latter is the formation of the third embryonic layer, the mesoderm

The term gastrulation means the formation of gut (Greek, gastrula = belly), but has now a more broad sense to to describe the formation of the trilaminar embryo. The epiblast layer, consisting of totipotential cells, derives all 3 embryo layers: ectoderm, mesoderm and endoderm. The primitive streak is the visible feature which represents the site of cell migration to form the additional layers.

primitive node – region in the middle of the early embryonic disc epiblast from which the primitive streak extends caudally (tail)

◦nodal cilia establish the embryo left/right axis

◦axial process extends from the nodal epiblast

—primitive streak – region of cell migration from the epiblast layer forming sequentially the two germ cell layers (endoderm and mesoderm)

Epithelial to Mesenchymal Transition

Epithelial cells (organised cellular layer) which loose their organisation and migrate/proliferate as a mesenchymal cells (disorganised cellular layers) are said to have undergone an Epithelial Mesenchymal Transition (EMT).

Mesenchymal cells have an embryonic connective tissue-like cellular arrangement, that have undergone this process may at a later time and under specific signalling conditions undergo the opposite process, mesenchyme to epithelia. In development, this process can be repeated several times during tissue differentiation.

This process occurs at the primitive streak where epiblast cells undergo an epithelial to mesenchymal transition in order to delaminate and migrate.

…………………………………………….

– Period: The third week (week 3) following fertilization or clinical gestational age GA week 5, based on last menstrual period.

Note that during this time the conceptus cells not contributing to the embryo are contributing to placental membranes and the early placenta.

During the third week of development conceptus implantion in the uterus wall is complete and trophoblast cells continue to invade uterine wall in the process of early placentation (villi formation). Within the conceptus, gastrulation converts the bilaminar embryo into the trilaminar embryo (ectoderm, mesoderm, endoderm). Morphological changes include an epithelial to mesenchymal cell transition and folding of the embryonic disc.

Outside of the embryo, the extraembryonic spaces (chorionic, amniotic, yolk) and intraembryonic spaces (coeloms) continue to develop. Trophoblast cells continue to invade uterine wall and the emdometrium is being converted into the decidua, the process of villi formation and early placentation has begun.

Week 3 of Development: The Notochord, Neural Tube, and Allantois

Formation of the 3 germ layers occurred in a cephalocaudal direction, this means that the 3 germ layer are establish first in the head region then the tail region. Also tissues and organs develop in a cephalocaudal direction.

Notochord development:  in the human, the notochord is a cellular rod that develops from the prochordal process and forms the first longitudinal midline axis around which the vertebral bodies are organized and is the basis for the axial skeleton. It will later regress.

By day 12 or 13, the notochord is visible throughout the length of the embryo and around it are layered concentrations of cells, representing the primordia of the future vertebral bodies.

Notochord Development

1. STAGE OF THE NOTOCHORDAL PROCESS (entire area cephalic to the primitive streak):  about day 17

• The floor of the notochordal process fuses with the underlying endoderm as it undergoes preferential growth. Hensen’s node seems to recede toward the caudal end.

2. PROCHORDAL STAGE: about day 19

• Degeneration of the fused region takes place, and openings appear in the floor of the notochordal process (resorption of the floor), opening a communication between the yolk sac and the notochordal canal, a lumen which is formed as the primitive pit extends into the notochordal process during its development

The openings become confluent, and the floor of the notochordal canal disappears. A small passage, the neurenteric canal, temporarily connects the yolk sac and the amniotic cavity

3. NOTOCHORD STAGE: about day 20

• The notochord process remains and forms a grooved, flattened plate, the notochordal plate, which, beginning at its cranial end, infolds to form the notochord. The embryonic endoderm again forms a continuous layer below the notochord The latter is thus the primary skeleton of the 3-layer embryo.

Neural tube development (neurulation)

1. THE EMBRYONIC ECTODERM over the developing notochord thickens to form a neural plate (about day 18) which apparently is enduced by the developing notochord and paraxial mesoderm on either side

• The plate first appears cranial to the primitive knot and dorsal to the notochordal process with mesoderm adjacent to it
• With the elongation of the notochordal process, the neural plate broadens and extends cranially to the oropharyngeal membrane
• The ectoderm of the plate is called neuroectoderm and eventually gives rise to the central nervous system (brain and spinal cord)

2. THE NEURAL PLATE, on about day 20, invaginates along its central axis to form the neural groove with neural folds created on each side of the groove

• By the end of week 3, the neural folds move together, fuse, and convert the neural plate into the neural tube. Closure begins in the middle of the embryo and progresses toward both cephalic and caudal ends. It begins on day 21
  • Closure of the neural groove is more rapid toward the cephalic (anterior) end than toward the caudal (posterior) end
    • The anterior or cranial neuropore closes in week 4 (day 26), whereas the posterior or caudal neuropore closes near day 28
  • Neuroectodermal cells at the lateral edge of the neural plate -do not become part of the tube but form a neural crest over the neural tube and give rise to the neural crest cells

The allantois

appears on day 16 as a small, finger like outpouching or diverticulum from the caudal wall of the yolk sac. It remains small in the human embryo, is involved with early blood formation, and is related to the development of the urinary bladder.

Functions of The Notochord

1.It forms the basis of the axial skeleton (bones of the head and vertebral column).

2. It induces the overlying ectoderm to thicken and form the neural plate; the primordium  of the central nervous system (Notochord is the organizer for nervous system formation) .

3. The notochord degenerates and disappears as the bodies of the vertebrae form. Its remnant is the nucleus pulposus of the intervertebral discs.

4. It functions as the primary inducer in the early embryo i.e. it is a prime mover in a series of signal-calling episodes that ultimately transform unspecialized embryonic cells into definitive adult tissues and organs

Clinical Application

Third week of development is a very sensitive period in foetal development. Many factors such as drugs, alcohol or irradiation to the mother may cause congenital anomalies to her embryo.

Week 3 of Development: Intraembryonic Mesoderm, Somite Development, and The Intraembryonic Coelom

Intraembryonic Mesoderm

The cells of the primitive streak& notochordal process proliferate—->2ry mesoderm —->migrate laterally & cranially between ectoderm& endoderm except oral membrane ( cranially) & cloacal membrane  (caudally).

The embryo now is called gastrula.

AS THE NOTOCHORD AND NEURAL TUBE FORM, the intraembryonic mesoderm on each side forms longitudinal columns, the paraxial mesoderm, each in turn being continuous laterally with the intermediate mesoderm, and the latter gradually thinning out further laterally into the lateral mesoderm.

Paraxial Mesoderm and Somite Formation

somite development begins about day 20 and is the result of segmentation of the paraxial mesoderm

A. The paraxial mesoderm thickens and fragments metamerically, dividing into paired cuboid bodies called somites which give rise to most of the axial skeleton and associated musculature as well as much of the dermis of the skin

B. The first pair of somites develops just caudal to the cranial end of the notochord (future occipital area), and subsequent pairs form in a craniocaudal sequence after the appearance of the first somites

C. About 38 somite pairs form during days 20-30, the so-called somite period. Eventually about 42-44 somite pairs develop by the end of week 5

1. The somites form distinct surface elevations and are triangular in shape when seen in a transverse section
2. Each somite develops a slitlike cavity, the myocele, which eventually is occluded
3. Somites give origin to the sclerotome, whose cells condense around the notochord and give rise to the vertebral primordia and the myotome, which gives rise to the vertebral muscles
   • The myotome with the somatopleure gives origin to the muscles of the limbs and the anterior lateral body walls

The intraembryonic coelom

The intraembryonic coelom first appears as many small isolated coelomic spaces in the lateral mesoderm and cardiogenic mesoderm (between the 2 layers of the lateral plate mesoderm) which coalesce to form a horseshoe-shaped cavity, the intraembryonic coelom, which is lined by flattened epithelial (mesothelial) cells. It will become the pleuropericardial-peritoneal cavity

◦THE COELOM DIVIDES the lateral mesoderm into 2 layers: a somatic (parietal) layer continuous with the extraembryonic mesoderm over the amnion and a splanchnic (visceral) layer, which is continuous with the extraembryonic mesoderm over the yolk sac

• Somatic mesoderm plus overlying embryonic ectoderm forms the body wall or somatopleure
• Splanchnic mesoderm plus embryonic entoderm forms the wall of the primitive gut and is called the splanchnopleure

◦DURING THE SECOND MONTH, the intraembryonic coelom is divided into the body cavities, namely, the pericardial cavity, the pleural cavities, and the peritoneal cavity

Week 3 of Development: Cardiovascular System Development

A.  Angiogenesis or blood formation begins in the extraembryonic mesoderm of the yolk sac, connecting stalk, and chorion during days 13-15. The embryonic vessels begin to develop approximately 2 days later

◦MESENCHYMAL CELLS or angioblasts aggregate to form isolated masses and cords called blood islands

1. Spaces accumulate in the islands, angiob1asts arrange themselves around the cavities to form the primitive endothelium, then isolated vessels fuse to form networks of endothelial channels

2. Vessels continue to extend into adjacent areas by endothelial budding and fusion with other vessels being formed independently

B. Blood cells and primitive plasma develop from the endothelial cells as the vessels develop on the allantois and yolk sac

1. BLOOD FORMATION begins in week 5, occurring in various portions of the embryonic mesenchyme, particularly in the liver, then later in the spleen, bone marrow, and lymph nodes

2. MESENCHYMAL CELLS around the primitive endothelial vessels differentiate into the muscles and connective tissue of the blood vessels

3. THE PRIMITIVE ENDOTHELIAL CARDIAC TUBES form from mesenchymal cells in the cardiogenic area

• Longitudinally paired endothelial channels, the heart tubes, develop before the end of week 3 and begin to fuse into the primitive heart tube
• By day 21, the paired tubes link up with blood vessels in the embryo, connecting stalk, chorion, and yolk sac to form a primitive cardiovascular system. The cardiovascular system is the first organ system to reach a functional state
• Blood circulation usually is started by the end of week 3

Week 3 of Development: Trophoblast and Villus Development

1. THE TROPHOBLAST is characterized by many primary stem villi, consisting of a cytotrophoblast core covered by a syncytial layer, at the beginning of week 3

• With development, mesodermal cells from the extraembryonic somatopleuric mesoderm or cytotrophoblast penetrate the core of the primary villi and grow in the direction of the decidua to form the secondary stem villi which consist of a loose connective tissue core covered by a cytotrophoblastic layer which, in turn, is covered by a thin syncytial layer

2. BY THE END OF WEEK 3, mesodermal cells in the villus core differentiate into blood cells and small blood vessels, forming the villous capillary system, and thus create the tertiary villi

• By week 4, the tertiary villi are seen over the entire surface of the chorion
• The capillaries in the tertiary villi contact capillaries developing in the mesoderm of the chorionic plate and in the connecting stalk, eventually contact the intraembryonic circulatory system, and connect the placenta and the embryo. Thus, in week 4, when the heart begins to beat, the villous system is able to supply the embryo with oxygen and nutrients, whereas prior to that time it was all done by diffusion

3.  CYTOTROPHOBLAST CELLS in the villi penetrate the overlying syncytium to reach the maternal endometrium

• They establish contact with similar extensions of neighboring villous stems to form a thin outer cytotrophoblast shell
  • The cytotrophoblast shell is seen on the embryonic pole initially and then expands toward the abembryonic pole until it covers the entire trophoblast, thus attaching the chorionic sac firmly to the maternal endometrial tissue
• Villi attached to the maternal tissues via the trophoblastic shell are called stem or anchoring villi
• Villi that grow from the sides of the stem villi are called branch villi, and it is through these that the major exchange of materials between the mother and the embryo takes place

4. BY DAYS 19 AND 20, the extraembryonic coelom or chorionic cavity enlarges, and the embryo is attached to its trophoblast shell only by a narrow connecting stalk

• The stalk is composed of extraembryonic mesoderm which is continuous with the chorionic plate and is attached to the embryo at its caudal end

The connecting stalk or body stalk later develops into the umbilical cord to connect the placenta and the embryo

Functions of the villi

1.Nutrition of the embryo (free villi).

2.Fixation of the embryo (anchoring villi).

3.Respiration of the embryo.

4.Excretion of the embryo.

– With development of the embryo, the chorionic villi toward the decidua basalis grow and become well developed. So the chorion there is called chorion frondosum.

– While the villi toward the decidua  capsularis become poorly developed, the chorion there is called chorion leava.