Third Week of Development – Anatomy, Types, Functions

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Third Week of Development/The third week is concerned with establishing left and right handedness, the craniocaudal axis, as well as the conversion of the bilaminar disc into a trilaminar embryo. Additionally, there is further specialization of the extraembryonic structures that will continue to support the embryo during the intrauterine phase.


During gastrulation, the embryo develops three germ layers (endoderm, mesoderm, and ectoderm) that differentiate into distinct tissues.

Key Points

Gastrulation takes place after cleavage and the formation of the blastula. Formation of the primitive streak is the beginning of gastrulation. It is followed by organogenesis—when individual organs develop within the newly-formed germ layers.

The ectoderm layer will give rise to neural tissue, as well as the epidermis.

The mesoderm develops into somites that differentiate into skeletal and muscle tissues, the notochord, blood vessels, dermis, and connective tissues.

The endoderm gives rise to the epithelium of the digestive and respiratory systems and the organs associated with the digestive system, such as the liver and pancreas.

Key Terms

  • somite: One of the paired masses of mesoderm, distributed along the sides of the neural tube, that will eventually become dermis, skeletal muscle, or vertebrae.
  • gastrulation: The stage of embryonic development at which a gastrula is formed from the blastula by the inward migration of cells.
  • notochord: A structure found in the embryos of vertebrates from which the spine develops.
  • epiboly: One
    of many movements in the early embryo that allow for dramatic physical restructuring and is characterized
    by a thinning and spreading of cell layers.

Gastrulation is a phase early in the embryonic development of most animals during which the single-layered blastula is reorganized into a trilaminar (three-layered) structure known as the gastrula. These three germ layers are known as the ectoderm, mesoderm, and endoderm.

This is a diagram of the formation of the three primary germ layers—ectoderm, mesoderm, and endoderm—that occurs during the first two weeks of development. The embryo at this stage is only a few millimeters in length.

Gastrulation: Formation of the three primary germ layers occurs during the first two weeks of development. The embryo at this stage is only a few millimeters in length.

Gastrulation takes place after cleavage and the formation of the blastula and the primitive streak. It is followed by organogenesis, when individual organs develop within the newly-formed germ layers. Each layer gives rise to specific tissues and organs in the developing embryo.

In amniotes such as humans, gastrulation occurs in the following sequence

  • The embryo becomes asymmetric.
  • The primitive streak forms.
  • Cells from the epiblast at the primitive streak undergo an epithelial to mesenchymal transition and ingress at the primitive streak to form the germ layers.

The ectoderm gives rise to the epidermis, and also to the neural crest and other tissues that will later form the nervous system. The mesoderm is found between the ectoderm and the endoderm, giving rise to somites.

The somites form muscle, the cartilage of the ribs and vertebrae, the dermis, the notochord, blood and blood vessels, bone, and connective tissue.

The endoderm gives rise to the epithelium of the digestive and respiratory systems, and the organs associated with the digestive system, such as the liver and pancreas. Following gastrulation, the cells in the body are either organized into sheets of connected cells (as in epithelia), or as a mesh of isolated cells, such as mesenchyme.

The molecular mechanism and timing of gastrulation is different in different organisms. However, some common features of gastrulation across triploblastic organisms include:

  • A change in the topological structure of the embryo, from a simply connected surface (sphere-like), to a non-simply connected surface (torus-like)
  • The differentiation of cells into one of three types (endodermal, mesodermal, or ectodermal).
  • The digestive function of a large number of endodermal cells.

Although gastrulation patterns exhibit enormous variation throughout the animal kingdom, they are unified by the five basic types of cell movements that occur during gastrulation:

  • Invagination
  • Involution
  • ingression
  • Delamination
  • Epiboly


Following gastrulation, the neurulation process develops the neural tube in the ectoderm, above the notochord of the mesoderm.

Key Points

The notochord stimulates neurulation in the ectoderm after its development.

The neuronal cells running along the back of the embryo form the neural plate, which folds outward to become a groove.

During primary neurulation, the folds of the groove fuse to form the neural tube. The anterior portion of the tube forms the basal plate, the posterior portion forms the alar plate, and the center forms the neural canal.

The ends of the neural tube close at the conclusion of the fourth week of gestation.

Key Terms

  • basal plate: In the developing nervous system, this is the region of the neural tube ventral to the sulcus limitans. It extends from the rostral mesencephalon to the end of the spinal cord and contains primarily motor neurons.
  • neurulation: The process that forms the vertebrate nervous system in embryos.
  • alar plate: The alar plate (or alar lamina) is a neural structure in the embryonic nervous system, part of the dorsal side of the neural tube, that involves the communication of general somatic and general visceral sensory impulses. The caudal part later becomes the sensory axon part of the spinal cord.
  • notochord: Composed of cells derived from the mesoderm, this provides
    signals to the surrounding tissue during development.
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Neurulation is the formation of the neural tube from the ectoderm of the embryo. It follows gastrulation in all vertebrates. During gastrulation cells migrate to the interior of the embryo, forming the three germ layers: the endoderm (the deepest layer), the mesoderm (the middle layer), and the ectoderm (the surface layer) from which all tissues and organs will arise.

In a simplified way, it can be said that the ectoderm gives rise to skin and the nervous system, the endoderm to the intestinal organs, and the mesoderm to the rest of the organs.

After gastrulation, the notochord—a flexible, rod-shaped body that runs along the back of the embryo—is formed from the mesoderm. During the third week of gestation the notochord sends signals to the overlying ectoderm, inducing it to become neuroectoderm.

This results in a strip of neuronal stem cells that runs along the back of the fetus. This strip is called the neural plate, and it is the origin of the entire nervous system.

The neural plate folds outwards to form the neural groove. Beginning in the future neck region, the neural folds of this groove close to create the neural tube (this form of neurulation is called primary neurulation).

The anterior (ventral or front) part of the neural tube is called the basal plate; the posterior (dorsal or rear) part is called the alar plate. The hollow interior is called the neural canal. By the end of the fourth week of gestation, the open ends of the neural tube (the neuropores) close off.

This is a series of illustrations of transverse sections that show the progression of the neural plate into the neural tube. The first illustration shows the neural plate as flat, laying atop the mesoderm and notochord. The second shows the neural plate bending down, with the tow tends joining at the neural plate borders, which are now referred to as the neural crest. The third shows the closure of the neural tube and how this disconnects the neural crest from the epidermis. The neural crest cells differentiate to form most of the peripheral nervous system. Finally, the notochord degenerates and other mesoderm cells differentiate into the somites.

Neurulation: Transverse sections that show the progression of the neural plate into the neural tube.

Secondary neurulation of vertebrates occurs when primary neurulation terminates. It is the process by which the neural tube at the lower levels and the caudal to the mid-sacral region is formed.

In general, it entails the cells of the neural plate forming a cord-like structure that migrates inside the embryo and hollows to form the tube. Each organism uses primary and secondary neurulation to varying degrees (except fish, which use only secondary neurulation).


Spina bifida is a developmental congenital disorder caused by the incomplete closing of the neural tube during neurulation.

This is an illustration of a child with spina bifida. An open defect is seen at the base of the child's spine. 

Spina bifida: An illustration of a child with spina bifida

Somite Development

Somites develop from the paraxial mesoderm and participate in the facilitation of multiple developmental processes.

Key Points

The paraxial mesoderm is distinct from the mesoderm found more internally in the embryo.

Alongside the neural tube, the mesoderm develops distinct paired structures called somites that develop into dermis, skeletal muscle, and vertebrae.

Each somite has four compartments: the sclerotome, myotome, dermatome, and the syndetome. Each becomes a specific tissue during development.

Key Terms

  • neural crest cells: A transient, multipotent, migratory cell population that gives rise to a diverse cell lineage including melanocytes, craniofacial cartilage, bone, smooth muscle, peripheral and enteric neurons, and glia.
  • conceptus: The fetus or embryo, including all the surrounding tissues protecting and nourishing it during pregnancy.
  • somite: One of the paired masses of mesoderm, distributed along the sides of the neural tube, that will eventually become dermis, skeletal muscle, or vertebrae.

Intraembryonic Coelom Development

In the development of the human embryo the intraembryonic coelom (or somatic coelom) is a portion of the conceptus that forms in the mesoderm. During the second week of development the lateral mesoderm splits into a dorsal somatic mesoderm (somatopleure) and a ventral splanchnic mesoderm (splanchnopleure).

By the third week of development, this process gives rise to a cavity between the somatopleure and splanchnopleure referred to as the intraembryonic celom. This space later gives rise to both the thoracic and abdominal cavities.

Somite Development

In the developing vertebrate embryo, somites are masses of mesoderm that can be found distributed along the two sides of the neural tube. They will eventually become dermis (dermatome), skeletal muscle (myotome), vertebrae (sclerotome), and tendons and cartilage (syndetome).

The mesoderm found lateral to the neural tube is called the paraxial mesoderm. It is separate from the chordamesoderm underneath the neural tube. The paraxial mesoderm is initially called the unsegmented
mesoderm in vertebrates, but is called the segmented mesoderm in chick embryos.

This is drawing of a dorsal view of a human embryo. The repetitive somites are marked with the older term primitive segments.

Somites: A dorsal view of a human embryo. The repetitive somites are marked with the older term primitive segments.

As the primitive streak regresses and the neural folds gather preceding the formation of the neural tube, the paraxial mesoderm divides into blocks called somites. Somites play a critical role in early development by participating in the specification of the migration paths of neural crest cells and spinal nerve axons.

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Later in development, somites separate into four compartments:


The dermatome is the dorsal portion of the paraxial mesoderm somite. In the human embryo it arises in the third week of embryogenesis.

The dermatomes contribute to the skin, fat, and connective tissue of the neck and of the trunk, though most of the skin is derived from the lateral plate mesoderm.


The myotome is that part of a somite that forms the muscles. Each myotome divides into an epaxial part (epimere), at the back, and a hypaxial part (hypomere) at the front.

The myoblasts from the hypaxial division form the muscles of the thoracic and anterior abdominal walls. The epaxial muscle mass loses its segmental character to form the extensor muscles of the neck and trunk of mammals.


The sclerotome forms the vertebrae and the rib cartilage and part of the occipital bone. It forms the musculature of the back, the ribs, and the limbs.


The syndetome forms the tendons and some blood vessels.

Development of the Cardiovascular System

The circulatory system develops initially via vasculogenesis, with the arterial and venous systems developing from distinct embryonic areas.

Key Points

The aortic arches are a series of six, paired, embryological vascular structures that give rise to several major arteries. The first and second arches disappear early. The third arch becomes the carotid artery.

The fourth right arch forms the right subclavian artery, while the fourth left arch forms the arch of the aorta. The fifth arch disappears on both sides.The proximal part of the sixth right arch persists as the proximal right pulmonary artery. The sixth left arch gives off the left pulmonary artery.

Approximately 30 posterolateral branches arise off the dorsal aortae and will form the intercostal arteries, the upper and lower extremity arteries, the lumbar arteries, and the lateral sacral arteries. The lateral branches of the aorta form the definitive renal, suprarenal, and gonadal arteries.

The ventral branches consist of the vitelline and umbilical arteries. The vitelline arteries form the celiac, and superior and inferior mesenteric arteries of the gastrointestinal tract. After birth, the umbilical arteries will form the internal iliac arteries.

The venous system develops from the vitelline veins, umbillical veins, and the cardinal veins, all of which empty into the sinus venosus.

Key Terms

  • sinus venosus: A large quadrangular cavity that precedes the atrium on the venous side of the chordate heart. In humans, it exists distinctly only in the embryonic heart, where it is found between the two venae cavae.
  • aortic arches: Also known as pharyngeal arch arteries, this is a series of six, paired, embryological vascular structures that give rise to several major arteries. They are ventral to the dorsal aorta.
  • cardinal vein: The precardinal veins or anterior cardinal veins contribute to the formation of the internal jugular veins and, together with the common cardinal vein, form the superior vena cava. In an anastomosis by anterior cardinal veins, the left brachiocephalic vein is produced.


The human arterial system originates from the aortic arches and from the dorsal aortae starting from week 4 of embryonic life.
The development of the circulatory system initially occurs by the process of vasculogenesis, the formation of new blood vessels when there are no preexisting ones.

This is a drawing of a profile view of a human embryo estimated at twenty or twenty-one days old. The six aortic arches are identified.

Embryonic cardiovascular system: A profile view of a human embryo estimated at twenty or twenty-one days old.

Vasculogenesis is when endothelial precursor cells (angioblasts) migrate and differentiate in response to local cues (such as growth factors and extracellular matrix) to form new blood vessels. The human arterial and venous systems develop from different embryonic areas.

Aortic Arches

The aortic arches—or pharyngeal arch arteries—are a series of six, paired, embryological vascular structures that give rise to several major arteries. They are ventral to the dorsal aorta and arise from the aortic sac.

Arches 1 and 2

This is a schematic drawing of the aortic arches and their arterial destinations.

Aortic arches: A schematic of the aortic arches and their arterial destinations.

The first and second arches disappear early, but the dorsal end of the second gives origin to the stapedial artery, a vessel that atrophies in humans, but persists in some mammals. It passes through the ring of the stapes and divides into supraorbital, infraorbital, and mandibular branches that follow the three divisions of the trigeminal nerve.

The infraorbital and mandibular branches arise from a common stem, the terminal part of which anastomoses with the external carotid. On the obliteration of the stapedial artery, this anastomosis enlarges and forms the internal maxillary artery; the branches of the stapedial artery are now branches of this vessel.

The common stem of the infraorbital and mandibular branches passes between the two roots of the auriculotemporal nerve and becomes the middle meningeal artery. The original supraorbital branch of the stapedial artery is represented by the orbital branches of the middle meningeal artery.

Arches 3 and 4

The third aortic arch constitutes the commencement of the internal carotid artery, and is named the carotid arch. The fourth right arch forms the right subclavian artery as far as the origin of its internal mammary branch. The fourth left arch constitutes the arch of the aorta between the origin of the left carotid artery and the termination of the ductus arteriosus.

Arches 5 and 6

The fifth arch disappears on both sides.The proximal part of the sixth right arch persists as the proximal part of the right pulmonary artery, while the distal section degenerates. The sixth left arch gives off the left pulmonary artery and forms the ductus arteriosus.

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This duct remains during fetal life, but closes within the first few days after birth due to increased O2 concentration. This causes the production of bradykinin which causes the ductus to constrict, occluding all flow. Within one to three months, the ductus is obliterated and becomes the ligamentum arteriosum.

Aortic Branches

The dorsal aortae are initially bilateral and then fuse to form the definitive dorsal aorta. Approximately 30 posterolateral branches arise off the aorta and will form the intercostal arteries, upper and lower extremity arteries, lumbar arteries, and the lateral sacral arteries.

The lateral branches of the aorta form the definitive renal, suprarenal, and gonadal arteries. Finally, the ventral branches of the aorta consist of the vitelline arteries and umbilical arteries.

The vitelline arteries form the celiac, and superior and inferior mesenteric arteries of the gastrointestinal tract. After birth, the umbilical arteries will form the internal iliac arteries.

The human venous system develops mainly from the vitelline, umbilical, and cardinal veins, all of which empty into the sinus venosus. The venous system arises during the fourth to eighth weeks of human development.


Most defects of the great arteries arise as a result of the persistence of aortic arches that normally should regress or due to the regression of arches that normally should not.

A double aortic arch occurs with the development of an abnormal right aortic arch, in addition to the left aortic arch, forming a vascular ring around the trachea and esophagus, which usually causes difficulty breathing and swallowing.

Occasionally, the entire right dorsal aorta abnormally persists and the left dorsal aorta regresses. In this case, the right aorta will have to arch across from the esophagus, causing difficulty breathing or swallowing.

Chorionic Villi and Placental Development

In the placenta, chorionic villi develop to maximize surface-area contact with the maternal blood for nutrient and gas exchange.

Key Points

Chorionic villi invade and destroy the uterine decidua while at the same time they absorb nutritive materials from it to support the growth of the embryo.

The villi begin primary development in the fourth week, becoming fully vascularized between the fifth and sixth weeks.

Placental development begins with implantation of the blastocyst; this leads to its differentiation into several layers that allow nutrient, gas, and waste exchange to the developing embryo and fetus —as well as forming a protective barrier.

Key Terms

  • chorion: The protective and nutritive membrane that attaches higher vertebrate fetuses to the uterus.
  • uterine decidua: The term for the uterine lining (endometrium) during a pregnancy, which forms the maternal part of the placenta. It is formed under the influence of progesterone and forms highly characteristic cells.
  • chorionic villi: These sprout from the chorion in order to give a maximum area of contact with the maternal blood.
  • placenta: A vascular organ present only in the female during gestation. It supplies food and oxygen from the mother to the fetus, and passes back waste. It is implanted in the wall of the uterus and links to the fetus through the umbilical cord. It is expelled after birth.

Chorionic Villi

Chorionic villi sprout from the chorion after their rapid proliferation in order to give a maximum area of contact with the maternal blood. These villi invade and destroy the uterine decidua while at the same time they absorb nutritive materials from it to support the growth of the embryo.

This is a schematic drawing of a chorionic artery. It shows the chorionic villi connecting to the maternal vessels.

Chorionic artery: An image showing the chorionic villi and the maternal vessels.

During the primary stage (the end of fourth week), the chorionic villi are small, nonvascular, and contain only the trophoblast. During the secondary stage (the fifth week), the villi increase in size and ramify, while the mesoderm grows into them; at this point the villi contain trophoblast and mesoderm.

During the tertiary stage (fifth to sixth week), the branches of the umbilical vessels grow into the mesoderm; in this way, the chorionic villi are vascularized. At this point, the villi contain trophoblast, mesoderm, and blood vessels.

Embryonic blood is carried to the villi by the branches of the umbilical arteries. After circulating through the capillaries of the villi, it is returned to the embryo by the umbilical veins. Chorionic villi are vital in pregnancy from a histomorphologic perspective and are, by definition, products of conception.


The placenta is a fetally derived organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother’s blood supply. The placenta begins to develop upon implantation of the blastocyst into the maternal endometrium.

The placenta functions as a fetomaternal organ with two components: the fetal placenta (chorion frondosum), which develops from the same blastocyst that forms the fetus; and the maternal placenta (decidua basalis), which develops from the maternal uterine tissue.

The outer layer of the blastocyst becomes the trophoblast, which forms the outer layer of the placenta. This layer is divided into two further layers: the underlying cytotrophoblast layer and the overlying syncytiotrophoblast layer.

The latter is a multinucleated, continuous cell layer that covers the surface of the placenta. It forms as a result of the differentiation and fusion of the underlying cytotrophoblast cells, a process that continues throughout placental development. The syncytiotrophoblast (otherwise known as syncytium) thereby contributes to the barrier function of the placenta.

This is a color image illustrating the placenta and chorionic villi. The umbilical cord is seen connecting the fetus to the placenta.

Placenta: Image illustrating the placenta and chorionic villi. The umbilical cord is seen connected to the fetus and the placenta.



Like many other phases of embryological development, gastrulation is a complex, biochemically dependent process by which the bilaminar embryo acquires a third layer to become a trilaminar disc. It is not uncommon to hear some individuals refer to the embryo as a gastrula during this developmental phase. During this process, the embryo also develops axial inclination. This process also contributes significantly to the morphological changes that the embryo will go through in order to acquire a human shape.

Steps and processes

Gastrulation begins when a linear region of cells of the epiblast layer become thicker at the caudal aspect of the embryo. This primitive (Spemann’s) streak develops as epiblast cells replicate and migrate to the midline of the bilaminar disc under the influence of nodal. Nodal is a transformation growth factor β (TGF β) protein that not only initiates, but also maintains the primitive streak. The streak is comprised of totipotent stem cells from the epiblast that grow in a caudocranial manner. As cells are added to the caudal end of the primitive streak, the cranial end begins to enlarge and forms a primitive (Hensen’s) node.

The primitive node (and streak) is maintained by the hepatocyte nuclear factor 3β (HNF-3 β; a product of the FOXA2 gene). The presence of this protein is also crucial for the formation of forebrain and midbrain structures as well. Simultaneously, a slender depression develops within the streak that is continuous with the sunken area at the primitive node (i.e. the primitive groove and primitive pit, respectively). The establishment of these structures allow identification of the cranial (near the primitive node) and caudal (towards the tail of the primitive streak) poles of the embryo. It also facilitates the identification of the left and right sides, as well as dorsal and ventral surfaces of the embryo.

Germ layers


The cells of the primitive streak synthesize and secrete fibroblast growth factor 8 (FGF8). FGF8 downregulates the expression of E-cadherin, which is intended to promote cellular adhesion. As a result, epiblast cells that have lost their adhesion molecules will subsequently undergo invagination. Not only does this give rise to the previously described depressions (primitive groove and pit), but it also results in migration of epiblast cells between the epiblast and the hypoblast layers. These cells lose their tall columnar appearance and become loosely arranged spindle-shaped cells suspended in collagenous reticular fibers known as mesenchyme. The mesenchyme is made up of pluripotent cells that will provide structural support for the embryo. They also have the ability to differentiate into osteoblasts, chondroblasts, and fibroblasts, in addition to participating in vasculogenesis and angiogenesis.

FGF8 stimulates the expression of another protein, called Bachyury T, which regulates the transformation of other mesenchyme cells to the middle embryonic layer known as the mesoderm. As other epiblast and primitive streak cells migrate deeper, they eventually displace cells of the hypoblast to form the embryonic endoderm. The cells remaining in the epiblast are subsequently referred to as the ectoderm. Therefore, all three germ layers of the gastrula are epiblast derivatives. The mesoderm will eventually separate the ectoderm from the endoderm, except at the points where the two layers are fused (i.e. caudally at the cloacal membrane, and cranially at the prechordal plate). The cloacal membrane is a circular structure that marks the future location of the anus. On the other hand, the prechordal plate gives rise to the oropharyngeal membrane (also a bilaminar region), which will form the future mouth and pharynx.


The three germ layers are responsible for forming all tissues within the body. The fate of each layer is as follows:

  • The embryonic ectoderm, which is located on the dorsal surface of the embryo, is subdivided into neural ectoderm and surface ectoderm. The neural ectoderm will give rise to the sensory organs (eyes, internal ears). It also subdivides into the neural tube (which will form the brain and spinal cord) and the neural crest (which differentiates into the head mesenchyme and the peripheral nervous system). The surface ectoderm develops into the epidermis.
  • Embryonic mesoderm is a bit more diverse and gives rise to paraxial, intermediate, and lateral plate mesoderm. The lateral plate mesoderm has cardiac, haematological, vascular, and smooth muscle fates. It also gives rise to the spleen, lymphatics, and adipose tissue. Intermediate mesoderm is responsible for the formation of the lower urinary tract, kidneys, and the reproductive system.  The paraxial mesoderm first form somites. The somites then differentiate into the rigid structural components of the body (i.e. bone, ligaments and tendons, cartilage and skeletal muscle). They also give rise to the dermis.
  • The embryonic endoderm gives rise to the aero-digestive epithelium, as well as the glandular cells of the gastrointestinal tract and its associated organs. The lungs, thymus, thyroid, and prostate glands are also derived from endoderm.

Primitive streak cells continue to migrate and differentiate into mesoderm up until the beginning of the 4th gestational week. As mesoderm production declines, the primitive streak also begins to regress, becoming a small structure in the sacrococcygeal part of the embryo. Eventually, it completely disappears by the end of week 4.

Notochord formation

Steps and processes

As the primitive node and streak are formed, invaginating mesodermal cells migrate cranially through the structure. They become prenotochordal cells that travel cranially towards the prechordal plate, in the midline. The primitive pit then projects into the notochordal process, giving rise to the notochordal canal. The notochordal process is now a tubular structure occupying the space between the primitive node to the prechordal plate. The prenotochordal cells of the notochordal process interdigitate with the cells of the hypoblast layer, prior to the invasion of the endoderm. The fused layer subsequently becomes perforated, allowing communication between the notochordal canal and the umbilical vesicle. As these perforations coalesce, the floor of the notochordal canal is lost. This is followed by flattening of the remaining notochordal process to form the notochordal plate.

Proliferation of the notochordal cells at the cranial end of the notochordal plate results in infolding of the tubular structure. Subsequently, a solid cord of cells that is definitively the notochord arises. At the area where the primitive pit descends into the epiblast, the notochordal canal persists; giving rise to a neurenteric canal that provides temporary communication between the amniotic cavity above and the umbilical vesicle below. This communication is obliterated as the notochord detaches from the endoderm.

The notochord projects from the primitive node to the oropharyngeal membrane. As the primitive streak extends caudally, the notochord also follows. Therefore, a craniocaudal growth pattern of the notochord is observed. Also, note that at this stage of development, prechordal mesoderm arises from neural crest cells, just rostral to the notochord. Therefore, the cloacal and oropharyngeal membranes are the only bilaminar regions of the embryo that remain. Notochordal migration is also associated with movement of pluripotent mesoderm that also move cranially, bilaterally with respect to the notochord process and prechordal plate. Once they have established a cranial position in the cardiogenic area of the embryo, the heart primordium is formed from the cardiogenic mesoderm by the end of week 3.

Functions of the notochord

The functions of the notochord in the development of the embryo are as follows:

  • It defines the primitive longitudinal axis of the embryo.
  • It provides some rigidity to the fragile developing human.
  • It contributes to the formation of the intervertebral discs. Fragments of the notochord persist into adulthood as the nucleus pulposus of the intervertebral disc.
  • It plays an important role in the formation of the axial musculoskeletal system.
  • It is important in the development of the central nervous system.

Neural tube development

Steps and processes

Not only does the notochord influence the epiblast to migrate and form the two deeper layers, but it also stimulates regions of the ectoderm to form the neural plate. This thick, elongated area of epithelial cells is a midline structure is adjacent to the midline and is superficially related – and equal in length – to the notochord. Growth of the notochord corresponds with an increase in width of the neural plate. The plate also grows cranially and meets the oropharyngeal membrane until it eventually outgrows the notochord. There is a prominent invagination along the long axis of the neural plate called the neural groove.

Development of the Notochord
Development of the notochord

There are raised neural folds on either side of the groove that appear more pronounced at the cranial pole; indicating early brain development has commenced. Inward migration and subsequent fusion of the neural folds occur as the third week comes to a close. The neural plate has now become a neural tube, which serves as the primitive spinal cord and brain vesicles. Some neural crest cells that were not incorporated in the neural tube transform from epithelium to mesenchyme, after which they move away from the fusing neural folds. The underlying neural tube separates from the ectoderm and the non-neural edges of the ectoderm fuse to close the dorsum of the embryo; forming the epidermis.

During the closure of the neural tube, there is dissociation of some underlying neuroectodermal cells at the inner border of the folds. The neural crest cells completely separate from both the surface ectoderm and neural tube during this migration process. They aggregate as flat, irregular cells known as the neural crest that lies between the neural tube and surface ectoderm. The neural crest divides into left and right halves and migrates laterally, to the dorsal region of the embryo (relative to the neural tube).


They then develop into sensory ganglia of cranial (CN V, VII, IX, and X) and spinal (dorsal root) nerves. Other structures that are derived from the neural crest include, but are not limited to:

  • Neurilemma sheaths of peripheral nerves
  • Leptomeninges of the arachnoid mater and pia mater
  • Pigment cells
  • The medulla of the suprarenal glands

Importantly, the neural tube contributes significantly to lateralization. The floor of the neural tube expresses the LEFTY protein on the left side of the embryo. Studies suggest that it restricts crossing over of left-sided signals to the right.

Lateralization and body axis formation

While the human body has some amount of symmetry to it (with several organs being paired; each occurring on one side of the body), there are other organs that possess a certain degree of asymmetry and only exist on one side. Lateralization refers to the establishment of left and right sidedness of the body. It occurs as a result of particular genes only being expressed on the left side, and others being silenced on the right.

These events begin prior to the gastrulation phase. The activity of anterior visceral endoderm (AVE) is an example of axial development that precedes gastrulation. The AVE is located at the cranial aspect of the embryonic disc and is integral in the formation of the head. It regulates the expression of LIM homeobox 1 (LHX1), homeobox expressed in ES cells 1 (HESX1), and orthodenticle homeobox 2 (OTX2); which, along with other factors establish the cranial region of the disc. The protein nodal (mentioned previously) also stimulates the production of other gene products that help to define the dorsoventral mesoderm, as well as other cranial and caudal structures.

Bone morphogenetic protein 4 (BMP4) also works in conjunction with fibroblast growth factors to shift mesodermal cells to the ventral region of the body cavity. This ensures that structures such as the body wall mesoderm, blood mesoderm (arising from lateral plate mesoderm) and the kidneys (originating from intermediate mesoderm) will be formed in the ventral area. The impact of BMP4 on the mesoderm is regulated by other genes (noggin, follistatin and Goosecoid) expressed in the primitive node; otherwise, all mesodermal structures would be ventralized.

The Bachyury T gene also participates in the formation of dorsal mesoderm in both the midline and tail region of the embryo. Its gene products are transcription factors that bind to DNA binding domains (T-box), which aid in dorsal and caudal mesoderm formation.

Earlier it was mentioned that nodal is important for the formation of the primitive node and streak. Additionally, these structures also secrete the nodal protein under the influence of FGF8, but only of the embryo’s left side. This is an important factor in the lateralization process. FGF8 induced nodal expression also persists later in embryonal development in the lateral plate mesoderm in addition to the LEFTY-2 (left-right determination factor 2) protein. Both LEFTY-2 and nodal proteins work synergistically to upregulate the expression of another homeobox transcription factor, PITX2 (paired like homeodomain 2) that aids in defining left sidedness. It should be noted that organs found predominantly on the left side of the body (i.e. the primordia of the gut, stomach, heart) are particularly exposed to these left sided proteins.


By the 16th day of gestation, an outpouching extending from the wall of the umbilical vesicle that is adjacent to the connecting stalk develops. This diverticulum is referred to as the allantois. In humans, it is a rudimentary structure that may be linked to pathological processes of the urinary bladder.

The allantoic mesoderm spreads out deep to the chorion and expresses vasculogenic potential; giving rise to the umbilical artery that will supply the placenta (the umbilical vein arises from another source). Proximally, the allantois persists throughout development as the urachus. This structure connects the urinary bladder to the anterior abdominal. In adults, the urachus is known as the median umbilical ligament.

Medial umbilical ligament
Medial umbilical ligament

Somite formation

Primitive node tissues are also responsible for the formation of paraxial mesoderm. These are longitudinal blocks of cells that are medially related to the intermediate mesoderm. For completion, the lateral mesoderm is lateral to the intermediate mesoderm, but medial to the extraembryonic mesoderm of the umbilical vesicle and amnion. Under the influence of forkhead transcription factors (FoxC1 and FoxC2), along with NOTCH and HOX genes, condensation and conformational changes of the paraxial mesoderm cells at the end of week three gives rise to paired cube-like bodies of cells called somites.

This development takes place craniocaudally – thanks to the Delta-Notch signalling pathway – on either side of the neural tube. By week four, the embryo will enter the somite period, where around 38 pairs of somites can be observed. This number increases to about 44 pairs by the end of week 5. Somites are unique because they produce marked elevations on the dorsal surface of the embryo. Their prominence also aids in aging the embryo during the fourth and fifth gestational weeks.

Intraembryonic coelom

coelom refers to a body cavity. Therefore the intraembryonic coelom is the primitive body cavity within the embryo. Initially, they appear as solitary coelomic spaces in the lateral and cardiogenic mesoderm layers. Subsequent fusion of the spaces forms a solitary, horseshoe-like space that partitions the lateral mesoderm into two layers:

  • The splanchnic lateral mesoderm is the visceral layer that is adjacent to the endoderm layer and communicates laterally with the extraembryonic mesoderm of the umbilical vesicle. Together, the two structures will form the splanchnopleure; which is the embryonic gut.
  • The somatic lateral mesoderm is the parietal layer that is just deep to the ectoderm and communicates laterally with the extraembryonic mesoderm of the amnion. The two layers combine to form the somatopleure; also known as the embryonic body wall.

The intraembryonic coelom undergoes further division from the 5th gestational week, onwards. At that time, it is divided into the pericardial cavityperitoneal cavity, and the pleural cavities.

Primitive cardiovascular system

The conversion of a bilaminar embryonic disc to a trilaminar one reduces the efficacy of diffusion as the principal mode of nutrient delivery to the developing cells. Consequently, during the third week, the embryo initiates a more efficient mechanism for nutrient transport and waste disposal. Blood vessels arise by two major mechanisms: vasculogenesis and angiogenesis. The former refers to the formation of new blood vessels via a de novo pathway (i.e. induction and assembly of angioblasts). The latter, however, speaks to the formation of new blood vessels by budding from previously formed vessels. The development of blood itself is referred to as hematogenesis.

Blood and blood vessel formation

Fibroblast growth factor 2 (FGF2) is the primary instigator for vasculogenesis. By binding to fibroblast growth factor receptors (FGFR) on mesoderm, it induces their differentiation into hemangioblasts. These pluripotent cells then aggregate in the yolk sac and give rise to blood islands. With the action of vascular endothelial growth factor (VEGF) acting on vascular endothelial growth factor receptors (VEGF-R2), hemangioblasts eventually differentiate into endothelial cells. VEGF then acts on VEGF-R1 in order to stimulate the characteristic tubular arrangement of the endothelial cells in the blood vessels.The hemangioblasts that did not contribute to vasculogenesis will have one of two options:

  • The peripheral cells can give rise to angioblasts that will participate in angiogenesis.
  • Centrally located cells can become hematopoietic stem cells that will differentiate into all blood cells.

Vasculogenesis commences in the extraembryonic mesoderm of the connecting stalk, umbilical vesicle and chorion. It is followed briskly by embryonic vasculogenesis.

Primitive heart formation

As the blood and blood vessels begin to form, there is a concomitant establishment of the cardiogenic area. A pair of longitudinal tubes with endothelium called the endocardial heart tubes are formed during this time. They eventually fuse to form the primordial heart tube. It merges with embryonic and extraembryonic blood vessels to establish the primordial cardiovascular system. In most cases, heartbeats commence at the end of week three, making the heart the first functional organ of the embryo. However, this heartbeat is not readily appreciated until the 5th week of gestation.

Chorionic villi

The primary chorionic villi first appear as the 2nd week ended. Following this event, they are invaded by mesenchymal tissue as they began to arborize. The now secondary chorionic villi extend across the entire chorionic sac. These mesenchymal cells also have vasculogenic and hematogenic potential and subsequently differentiate into capillaries and blood cells. Once the blood vessels become visible, the structures are called tertiary chorionic villi. There is subsequent fusion of the capillaries that gives rise to the arterio-capillary network. These networks will eventually communicate with the primordial heart tube by the end of week . Fetomaternal exchange of nutrients and waste material can now be facilitated at the villous interface instead of the previous diffusion gradients. The trophoblast also continues to grow such that proliferation of the cytotrophoblast results in projection of the villi through the syncytiotrophoblast. This gives rise to an extravillous cytotrophoblastic shell that encircles the chorionic sac and further embeds into the endometrium.

Gross morphological changes of the embryonic disc

Not only does the embryonic disc now have three layers, but it has also increased in length and (in some areas) width. The previously flat circular disc elongates and becomes broad at the cephalic pole, but slender at the caudal region. The increased width at the cephalic end is attributed to the constant cellular migration to this area.

Trilaminar Embryo
Trilaminar embryo

The invagination migration sequence occurring at the primitive streak continues to progress into the 4th gestational week. It is interesting to note that while there is cessation of gastrulation cranially, the process persists in the caudal region. This phenomenon is related to the fact that cellular specialization in the cranial region precedes that same process caudally. Therefore, the primitive streak continues to undergo growth and promote gastrulation in the caudal segment of the embryo.



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