Thomas A. Marino, Ph.D.

Reading: Langman's Medical Embryology Chapters 3 - 5

Click
here to see a great list of embryology link prepared for the internet by Dr. Anna Ross at Christian Brothers University, Memphis, TN.

Click here to see a large but nicely done quicktime animation that encompases development from conception to birth from the University of Pennsylvania's Medical Website.

For ultrasound images of the developing human visit Dr. Joseph Woo's Website of Obstetric Ultrasound.

PREIMPLANTATION

After fertilization, the fertilized egg travels down the
uterine tube and the egg begins to undergo a series of divisions. These divisions begin during the second day. The first division is called cleavage. During the subsequent 2 days there continue to be a series of divisions and at this point the preembryo is called a morula. By day 5 the morula enters the uterus and a cavity begins to form. This initial cavity is called the blastocyst cavity. At the end of the first week of development the blastocyst enters the uterus and then attaches to endometrial endothelium. The blastocyst, at this point, consists of an embryoblast (inner cell mass) and a trophoblast. The trophoblast over the inner cell mass develops into two layers 1. a layer of cells that are mononucleate and lie closest to the inner cell mass called the cytotrophoblast, and 2. a layer formed by a multinucleate, syncytium of cells located outside the cytotrophoblast, called the syncytiotrophoblast. The future development of the trophoblast will be covered in the histology course.


The
inner cell mass, by the beginning of the second week, will begin to develop into a preembryonic two layer structure. The two layers consist of a layer of columnar cells called the epiblast and a second layer that lies closest to the blastocyst cavity called the hypoblast. It is following cell proliferation that a cavity appears within the epiblast and when it enlarges it becomes the amniotic cavity. The amniotic cavity is lined by cells that are derived mostly from the inner cell mass, but some cells may be derived from the trophoblast as well. The epiblast will give rise to the ectoderm, intraembryonic mesoderm, and the endoderm.

To view the first week you can visit
The Visible Embryo Project at the University of California at San Francisco.

At the opposite pole from the point where the embryo develops cells that were derived from the hypoblast line the blastocyst cavity which now changes its name and is called the exocoelomic cavity (primitive yolk sac). The cells form a membrane called the exocoelomic membrane (Heusner's membrane). During subsequent stages of development, there appears a population of cells that lie between the cytotrophoblast and the exocoelomic membrane. These cells give rise to the
extraembryonic mesoderm. As cavities develop in the extraembryonic mesoderm they coalesce and a new space is formed called the extraembryonic coelom (chorionic cavity,   click here for an animation of the cavity's formation by William Larsen). This cavity now surrounds the amnion and the yolk sac. When the extracoelomic cavity expands the mesoderm lining the cytotrophoblast is called the extraembryonic somatic mesoderm. The extraembryonic mesoderm lining the yolk sac is called the extraembryonic splanchnic mesoderm. There is one place where the extraembryonic mesoderm traverses the chorionic cavity and this is the connecting stalk that will become the umbilical cord.

For another view of the second week you can visit
The Visible Embryo Project at the University of California at San Francisco.


GASTRULATION AND NEURULATION

The main event that occurs during the third week of development is the formation of the trilaminar embryo. This process is called gastrulation. The first sign of gastrulation is the formation in the epiblast of the
primitive streak. The primitive streak is formed by the migration of epiblast cells to the midline, which then migrate under the epiblast. The cells that lie deep or inferior to the epiblast either replace cells that were in the hypoblast or else become located between this newly formed layer of cells and the epiblast. At this point a trilaminar disc is formed with the epiblast giving rise to all three germ layers: 1. the epiblast that remains becomes the ectoderm, the cells that replaced the hypoblast become the endoderm (entoderm), the cells in between becoming the mesoderm.


To view another perspective on the third week you can visit
The Visible Embryo Project at the University of California at San Francisco.

Some cells that invaginate in the primitive pit move in a cephalic direction. These cells form the
notochord. They continue forward until they reach the oral plate (prechordal plate) and form the notochordal (head) process. The oral plate is that area anterior to the notochordal process where ectoderm and endoderm are adjacent to each other without intervening mesoderm. As development continues, the cells of the notochordal process that are closest to the endoderm fuse with it leaving the upper cells that will eventually give rise to the notochord. The notochord lies between the endoderm and the ectoderm from the oral plate to the primitive node. Posterior to the primitive node is the neurenteric canal that connects the amniotic cavity with the yolk sac. Posterior to the neurenteric canal is the cloacal (anal) membrane (plate), another area where the endoderm and ectoderm meet without intervening mesoderm. Posterior to the cloacal membrane is a small diverticulum of the yolk sac, which invaginates into the connecting stalk. This is called the allantois.

DEVELOPMENT OF THE BODY AXIS

By the time the trilaminar disc is formed, the embryo has an anterior-posterior polarity as well as a dorsal-ventral polarity. One of the major questions is how the development of the body axis is regulated. It is thought that the body axis may arise as a result of local inducers or morphogens that act on cells to induce them to become secondary axis structures. Mesodermal cells are one of the first cells that can be induced to form either dorsal or ventral structures. It is known that different growth factors can be inductors of the mesoderm tissue. Factors such as activin A. (a member of the TGF-b family), basic fibroblast growth factor, and retinoic acid have been demonstrated to be involved in providing positional cues during early embryonic development. It remains to be elucidated how these factors work and the molecular basis for their function. However, important information also resides within the cells that are induced that may determine their fate. In addition, other information from other cells and other stimuli also may play an important role in directing the early migration of cells and their future lineage.

DEVELOPMENT OF THE ECTODERM

During the third week of gestation the ectoderm overlying the notochord begins to thicken and is called the
neural plate. As the embryo grows, the lateral edges along the length of the neural plate begin to elevate. The edges form the neural folds and the central region is called the neural groove. This process continues until the edges of the neural folds begin to meet in the midline and a neural tube is formed. This occurs first in the region of the presumptive neck and the neural tube then continues to form in both cephalic and caudal directions. As the ends of the neural tube close the process of neurulation is complete and the central nervous system is now represented by this closed hollow tube which is narrow caudally and larger and more dilated cephalically. The narrow caudal end represents the future spinal cord while the cephalic end represents the brain vesicles.

One question that arises concerns the mechanism by which the cells that will form the neural tube can be arranged, first as the neural plate and then become organized into a tube. This reorganization involves changes in cell shape. Those cellular changes are brought about by changes within the cell of its microtubules and microfilaments.
Microtubles can bring about cell elongation. At the same time microfilaments located at the most apical part of the cell can form a ring and cause the apical part of the cell to narrow. Thus, the cells can become pyramidal in shape, and this change in cell shape can alter a flat sheet of cells to become a hollow tube. The question then remains as to the nature of the stimulus that causes these particular cells to undergo these changes in cell shape. It is known that the notochord and the adjacent mesoderm around it can induce the ectoderm above to form the neural tube. How this induction process occurs and the cellular events underlying this event are not known at the present time.

During the formation of the neural tube, ectodermal cells that are at the junction of the neural plate with the surface ectoderm form
neural crest cells. During development these cells migrate extensively and give rise to a number of diverse cell types. The particular cell type that is formed is dependent upon the area where the cells migrate as well as where along the neural tube the cells arise. Cranial neural crest give rise to cells forming the trigeminal, facial, glossopharyngeal, and vagal sensory ganglia. These crest cells also give rise to the ciliary, pterygopalatine, submandibular and otic parasympathetic ganglia as well as ganglia associated with the vagus. Finally, these cells give rise to cartilage cells of the head and neck, ondontoblasts and mesenchymal cells that form bones of the skull. The neural crest cells associated with the neural tube that will form the spinal cord give rise to melanocytes, dorsal root sensory ganglia, the cervical, prevertebral and paravertebral sympathetic ganglia, the adrenal medulla, Schwann cells, and some parts of the meninges. In addition, there are contributions of neural crest cells to the wall of the aortic arches, the aorticopulmonary septum, the parathyroid, the carotid body and the thyroid. The pathway that the neural crest cells follow is thought to be influenced by the local environment in which the cells are located. Substances such a fibronectin, hyaluronic acid, or laminin appear to play a major role in directing the migration of neural crest.

Other central nervous system derivatives of the ectoderm include the retina, the Organ of Corti, the vestibular apparatus and the olfactory epithelium. These are all sensory neuroepithelial structures.

As the embryo develops and undergoes neurulation, the lateral edges of the embryo begin to fold ventrally and then turn toward the midline. Not only does the ectoderm move in this direction, but the lateral plate mesoderm, the intraembryonic coelom, the splanchnic mesoderm and the endoderm also move in this direction. The embryo at this point is said to be undergoing
lateral body folding. All three layers: ectoderm, somatic mesoderm, splanchnic mesoderm and endoderm will meet with the like components from the opposite side of the embryo. These structures will meet in the midline. This will leave the gut tube suspended by a mesentery lying in the body cavity. The gut tube will be surrounded by splanchnic mesoderm. The outside of the body cavity will be lined by somatic mesoderm which will lie deep to the ectoderm which forms the body wall.


To view another perspective of lateral body folding you can visit
The Visible Embryo Project at the University of California at San Francisco.

Outside the central nervous system and neural crest, the ectoderm gives rise to the epidermis and associated structures such as sweat glands, sebaceous glands, mammary glands, hair and nails. Structures associated with the oral cavity derived from ectoderm include the epithelia of salivary glands, enamel of teeth, covering of the tongue, anterior 2/3 of the oral cavity and part of the pituitary gland. The distal lining of the anal canal and the lining of the external auditory meatus is also derived from ectoderm. Finally, those structures associated with the eye that are derived from ectoderm include the anterior corneal epithelium, the glands associated with the eye, the lens, and pupillary muscles.

DEVELOPMENT OF THE MESODERM

During the third week of development the mesoderm on either side of the notochord thickens and is called the
paraxial mesoderm. Laterally, the mesoderm is thin and is called the lateral plate mesoderm. A cavity develops in the lateral plate mesoderm called the intraembryonic coelomic cavity. This cavity is continuous with the extraembryonic coelom. The mesoderm that lies dorsal to the intraembryonic coelomic cavity is called the parietal or somatic mesoderm. That mesoderm found ventral to the intraembryonic coelomic cavity is called the visceral or splanchnic mesoderm. The mesoderm between the paraxial and lateral plated mesoderm is called the intermediate mesoderm.

The paraxial mesoderm gives rise to somites, which then give rise to the axial skeleton and associated muscles, as well as the muscle of the extremities. In addition, paraxial mesoderm gives rise to the dermis.

The intermediate mesoderm gives rise to the kidneys and associated ducts, as well as the epididymis and vas deferens in the male, and the vagina, oviducts, uterus of the female.

The somatic mesoderm is derived from lateral mesoderm and gives rise to the parietal pleura, pericardium and peritoneum, the connective tissue and skeleton of the body wall. The splanchnic mesoderm also is derived from the lateral mesoderm. Those structures derived from the splanchnic mesoderm include the heart, blood vessels, and blood cells, stroma of the gonads, smooth muscle of viscera and blood vessels, the visceral pleura, pericardium and peritoneum, the mesenteries, as well as the cortex of the adrenal gland.

Finally the head mesenchyme is derived from cephalically located mesoderm and gives rise to the outer layers of the eye, muscles of the head, and some of the cartilage and connective tissue of the head.

DEVELOPMENT OF THE ENDODERM

When considering the development of the endoderm, it is important to recognize that during the beginning of the fourth week of gestation the embryo undergoes both
cephalocaudal folding (also known as flexion) as well as lateral (transverse) folding. During these events the flattened three layer embryo develops into an embryo in which the major features of the body form are now established. During cephalocaudal folding of the embryo, there is a rapid growth of the neural tube such that it becomes longer than the rest of the body. This rapid growth results in the movement of the head structures cephalically, and tail structures caudally, to rotate in a ventral direction. In the head region, structures that were cephalic to the neural tube initially rotate ventrally, so that the primitive heart and septum transversum now come to lie at first ventral, and then caudal to the prechordal plate (also called the oral plate or the buccopharyngeal membrane). In the tail region the neural tube soon lies caudal to the cloacal plate. With this cephalocaudal folding the foregut is now dorsal to the heart and septum transversum. The hindgut is dorsal to the allantois and the cloacal plate. The midgut at this time remains as an open connection with the yolk sac.

The
lateral body folding also plays an important role in the formation of the gut. With the continued growth of the mesoderm in the lateral directions the flat embryonic disc folds ventrally and then toward the midline to form the ventral abdominal wall. Only in the region of the midgut does a communication persist with the yolk sac. This is called the vitelline duct. As development continues, the allantois becomes partially incorporated into the embryo and forms the cloaca. The rest of the allantois, in the connecting stalk, and the vitelline duct in the yolk stalk fuse establishing the umbilical cord.

Structures that are derived from the endoderm include the epithelia of the trachea and bronchi, the lungs the gastrointestinal tract, pancreas, liver, urethra, and urinary bladder. The endoderm also gives rise to the pharynx from which is derived components of the thyroid, middle ear and auditory tube epithelia, thymus, parathyroids and tonsillar fossa.

For a small yet interesting listing and explanition of several known teratogens (substances which cause birth defects), check out the Mountain States Regional Genetic Services Network's Teratogen Update.