Weeks Three and Four
Overview
Weeks 3 to 8 constitute the embryonic period, a period in which the basic pattern of the major organ systems is laid out and the embryo transitions from being a flat disc to a more recognizable human form.
The hallmarks of this period are rapid cell division and differentiation; making the embryonic period particularly dangerous as the embryo is highly susceptible to the effects of teratogens in the environment and genetic disorders that may have been transmitted through the genome of either parent.
The third week of development is characterized by the initiation of several significant events that continue into week four and set the stage for subsequent development of tissues, organs and organ systems. These events begin with and include:
- Gastrulation
- Notochord Development
- Mesoderm Differentiation
- Neurulation
- Development of the Body Plan
- Folding of the Embryonic Disc
By the end of the 4th week, the embryo is poised to begin organogenesis.
The remaining four weeks of the embryonic period are devoted to development of the specific tissues, organs and organ systems. The Systems Development section of the web site will be the branching off point to explore the development of the specific organ systems, beginning around Week 5.
From the 8th week until birth is the fetal period, a time characterized by growth and functional maturation.
Gastrulation
The most significant event of one's life is not graduation from school, finding a career, marriage or buying a home; but rather, gastrulation.
By the end of gastrulation, the bilaminar embryo has been converted to a trilaminar embryo consisting of three primary germ layers:
- Ectoderm
- Mesoderm
- Endoderm
To fail gastrulation is to fail life.
Fig 1. Diagram showing the appearance of the primitive node and primitive streak at the onset of gastrulation and defining the cranial and caudal axis of the embryonic disc.
Primitive Node & Primitive Streak
Gastrulation begins early in week 3 with the appearance of the primitive streak and primitive node in the epiblast of the bilaminar embryonic disc.
The presence of primitive node and primitive streak establishes the cranio-caudal axis of the embryo.
During gastrulation epiblast cells migrate into the primitive streak and primitive node, where they , commit to form three new cell lines; endoderm, mesoderm and ectoderm.
In order to do this, epiblast cells must detach from the epithelial sheet by epithelial to mesenchymal transformation.
Fig 2. View looking down on the epiblast showing the primitive node and streak.
Epithelial to Mesenchymal Transformation
Cells of the epiblast form an epithelium held together by molecules called cadherins. Down regulation of the gene for cadherin allows the epiblast cells to separate from one another and become mobile mesenchymal cells.
Mesenchymal cells are able to migrate into the primitive streak and node during gastrulation.
In this way, cells of the epiblast generate the three primary germ layers:
- Ectoderm
- Mesoderm
- Endoderm
Fig 3. Animated gif illustrating how epithelial cells can leave the epiblast to become mobile mesenchymal cells through epithelial to mesenchymal transformation.
- Mesoderm specifically refers to the middle layer of the trilaminar (three layered) embryonic disc, formed during gastrulation.
- Mesenchyme refers to any loose collection of calls and can form from any of the three germ layers, though it is mostly formed by mesoderm.
Gastrulation Animation
The animation illustrates how epiblast cells move into the primitive streak to form a new layer of mesoderm between the ectoderm and endoderm.
Trilaminar Embryonic Disc
Successive waves of epiblast cells migrate into the primitive streak and primitive node, first to form endoderm followed by cardiogenic
mesoderm and finally, mesoderm.
As the primitive streak regresses, the remaining calls of the epiblast become the ectoderm.
At, the end of gastrulation the original bllaminar (two layered) embryonic disc, consisting of epiblast and hypoblast is converted to a trilaminar (three layered) embryonic disc consisting of three primary germ layers.
The primary colors are used in many embryology figures to denote derivatives of these three layers:
- ectoderm - blue
- mesoderm - red
- endoderm - yellow
Fig 4. Animated gif illustrating how the bilaminar embryonic disc, consisting of epiblast and hypoblast is converted to a trilaminar embryonic disc consisting of ectoderm, mesoderm and endoderm.
Looking down on the surface of the epiblast, which has been made transparent, successive generations of epiblast cells produce: endoderm, mesoderm and ectoderm.
After regression of the primitive node and primitive streak, endoderm and mesoderm undergo further differentiation.
Fig 5. Animated gif looking down on the surface of the embryonic disc illustrating how the epiblast, thought gastrulation gives rise to the three germ layers, endoderm, mesoderm and ectoderm
Notochord Development
Cranially, in the embryonic disc, endoderm cells contribute to the prechordal plate, an important organizing center for head and brain development.
Caudally, endoderm cells in the midline detach from the endoderm to form the notochord. Although the cells spend a short time living among the endoderm, the notochord is considered to be a mesoderm derived structure. I expect because of its resemblance to being the back bone of the embryo and its importance as an organizing center for development of the vertebral column.
Both, notochord and prechordal plate are organizing centers, that produce the morphogen, Sonic hedgehog (Shh)
Shh is essential for normal development of the brain and head region as well as the spinal cord, spine and major musculoskeletal elements of the torso and limbs.
Fig 6. At the end of gastrulation, endoderm cells in the cranial aspect of the embryo form the prechordal plate, an important organizing center for the head region of the embryo and the notochord and organizing center for the rest of the body.
Mesoderm Differentiation
Overview
A second wave of epiblast cells migrates from the primitive streak to the region cranial to the oropharyngeal membrane. These form the cardiogenic area where development of the heart will commence.
The final migration of epiblast cells during gastrulation results in the formation of the mesoderm.
Three masses of mesoderm are distributed on either side of the notochord. From medial to lateral they are:
- paraxial mesoderm
- intermediate mesoderm
- lateral plate mesoderm
In the gif to the right, we are looking down on the surface of the trilaminar embryonic disc to see the various regions of mesoderm deep to the surface ectoderm.
Fig 7. After its formation, mesoderm is regionally subdivided into cell groups that commit to specific developmental fates as seen in the cardiogenic region, paraxial, intermediate and lateral plate regions of mesoderm.
Fig 8. Cross section of an embryo near the end of week 4 and the subdivision of the intraembryonic mesoderm.
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Start Slide Show
Cardiiogenic Mesoderm
The cariogenic mesoderm forms in one of the earliest waves of gastrulation. Mesoderm migrates into the cranial region of the embryonic disc where it will begin development of the heart tube.
Fig 9a.
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Paraxial Mesoderm
Paraxial mesoderm becomes organized into segments known as somitomeres. Further organization of the cells results in blocks of tissue called somites.
The paraxial mesoderm (somites) contribute to the development of the axial skeleton; the skull and vertebral column and related muscles.
Fig 9b1.
Fig 9b2.
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Intermediate Mesoderm
Intermediate mesoderm contributes to the development of genitourinary structures such as the gonads, reproductive ducts, kidneys and ureters and bladder.
Fig 9c1.
Fig 9c2.
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Lateral Plate Mesoderm
The lateral plate mesoderm splits to form two layers.
One layer becomes affixed to the surface ectoderm as the parietal (somatic) layer of lateral plate mesoderm. It will form the musculoskeletal elements of the body wall and mesothelial lining of the body cavities.
The other layer becomes affixed to the endoderm as the visceral (splanchnic) layer of lateral plate mesoderm and will form the outer mesothelial covering of the visceral organs and connective tissue and smooth muscle of the walls of the hollow viscera.
Fig 9d1.
Fig 9d2.
Neurulation
Neurulation is the process that initiates development of the nervous system. It begins in the 3rd week with the appearance of the neural folds in response to sonic hedge hog (Shh), secreted by the notochord.
Fig 10.
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Start Slide Show
Under the influence of Sonic hedgehog (Shh) secreted by the notochord, midline surface ectoderm thickens to become neural ectoderm.
Fig 11a.
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The raised lateral edges of the neural ectoderm are called the neural folds.
Fig 11b.
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Neural folds become elevated and approach one another dorsally in the midline, surrounding the neural groove.
Fig 11c.
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Eventually the neural folds meet in the posterior midline, where they fuse to form the neural tube.
As the neural folds fuse, cells at the lateral edges undergo epithelial to mesenchymal transformation and become detached to form the neural crest.
Neural crest cells migrate throughout the body of the embryo to form components of the peripheral nervous system among other important tissues.
Fig 11d.
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Fusion of the neural folds produces the neural tube, that sinks beneath the surface ectoderm to eventually give rise to the brain and spinal cord.
Fig 11e.
Formation of the Neural Tube
The animation depicts the formation of the neural tube in the third and fourth weeks of development. Fusion of the neural folds begins in the middle of the embryo and proceeds simultaneously in rostral and caudal directions.
As the neural tube is completed, it sinks beneath the surface ectoderm where is it flanked on either side by blocks of paraxial mesoderm, the somites.
At the end of the process, the neural tube is divided into cranial and caudal sections that become the brain and spinal cord respectively.
More detailed development of the brain will be discussed in the Neuroscience thread.
Fig 12.
Neural Plate
This view is looking down on the embryonic disc at day 20 of development. The light blue represents the neural plate tissue that was induced to form from the surface ectoderm (dark blue) in the midline.
In the middle of the embryo, the neural groove is flanked by the neural folds, which have not yet fused.
Note that cranially, the neural plate is extending into the head region. Elongation of the neural tube is by a process known as convergent extension.
Convergent Extension
Convergent extension is the process that contributes to elongation of many structures during development. Among these are the primitive streak, notochord, gut tube and neural tube.
In convergent extension, cells that are laterally located in an epithelial sheet, merge into the midline, resulting in elongation of structure.
In the animation to the right, imagine eight lanes of traffic converging into two lanes in the middle of the highway to make one long lane of traffic.
Fig 13.
Neural Tube
Fig 14.
Fusion of the neural folds occurs simultaneously in rostral (cranial) and caudal directions (double headed red arrow).
At day 23, the middle of the neural tube has sunk beneath the surface ectoderm and is flanked on each side by somites.
Cranially, the unfused neural folds surround the anterior neuropore. Caudally, they surround the posterior neuropore.
Completion of the cranial end of the neural tube is around day 25 with closure of the anterior neuropore.
The caudal end of the neural tube is complete with closure of the posterior neuropore around day 28 at the end of the 4th week.
Failure of the anterior neuropore to close results in profound malformations of the brain and skull, a condition referred to a anencephaly. Failure of the posterior neuropore to close results in spina bifida, characterized by defects of the vertebrae of the caudal end of the vertebral column, meningeal herniation among others.
Neural Crest
Cells at the edges of the neural fold dissociate from the epithelial sheet as mesenchymal cells (epithelial-mesenchymal transformation).
They migrate throughout the body of the embryo as neural crest cells.
Neural crest cells respond to local environments to form a large number of tissues and structures during development.
They are critically important in development of the heart and craniofacial musculoskeletal structures as well as peripheral sensory and motor ganglia.
The table at the right lists most of the derivatives of neural crest, a list that is very much in flux.
Fig 15.
Development of the Body Plan
The universe is 3 dimensional and the body plan reflects this. Each of the three body axes; dorsal to ventral or posterior to anterior (blue), cranial (rostral) to caudal (caudad) (red) & medial to lateral (purple), is defined early in development, at specific times.
Fig 16.
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Start Slide Show
Fig 17.
The dorsal/ventral (posterior/anterior axis) is defined in Week 2 when the embryoblast forms two layers, epiblast (dorsal) and hypoblast (ventral).
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At the beginning of the third week, the cranial/caudal axis is established by the appearance of the primitive node and primitive streak at the caudal end of the embryonic disc.
Fig 18.
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Fig 19.
Finally, the side to side axis or medial/lateral axis is defined by the formation of the notochord in the midline of the trilaminar embryonic disc.
Although we appear bilaterally symmetrical on the outside, we are not.
Left/right asymmetry is important in the proper disposition and orientation of the internal body organs as some are more on the left and others on the right.
Left/right asymmetry is determined in the 3rd and 4th week by cilia on cells in the primitive node. These cilia beat in a clockwise direction producing a gradient of signal molecules (morphogens) on the left side of the embryonic disc that turn on genes to determine left sidedness and the appropriate placement of viscera within the body cavities.
Details of the this process will be discussed in the section on Molecular Regulation of Development.
Fig 20.
Embryonic Folding & Coelom Formation
Beginning in the third week and continuing into the fourth week, the embryo starts to transform from a disc shape to a cylindrical shape largely through folding in the sagittal plane and the transverse plane.
Due to an increase in the length of the embryo, the cranial and caudal regions of the embryo move farther away from one another. At the same time, the rapid growth of the neural tube and somites causes the lateral aspects of the embryo to fold inward.
The net effect is a closing off of the body cavity ventrally around a point centered on the umbilical like the strings of a purse.
This is referred to as a "tube within a tube" structure. The body assumes a "tubular" shape as do many of the internal organs, such as the digestive tract (often referred to as the "gut tube"), the nervous system, (referred to as the "neural tube") and the "heart tube".
Sagittal Folding
In the animation observe what appears to be a blue bubble sitting on top of a yellow bubble. The blue bubble is the surface ectoderm covered by the amnion. The yellow bubble is the endoderm lined yolk sac.
The connecting (body) stalk, which consists of extraembryonic mesoderm, attaches the embryo to the chorionic sac. At the end of the animation, the folding of the embryo has squeezed the yolk sac against the connecting stalk. As a result these structures come to be located within the umbilical cord.
Fig 21.
Transverse Folding
Fig 22.
In this animation note how the lateral plate mesoderm splits to create the intraembryonic coelom which is ultimately incorporated into the embryo.
Note that the gut tube is suspended from the posterior body wall by a sheet of mesoderm which will become the dorsal mesentery.
Although a ventral mesentery is present initially, it disappears from all but the foregut region of the gut tube.
The body itself assumes a tubular shape and within we see cross sections of the gut tube, the neural tube and the heart tube, all of which will undergo folding as they proceed through development.
Even the coelomic cavity is a tubular space extending through the length of the embryo, eventually to be separated into thoracic and abdominopelvic cavities.
Fig 23. Diagram of the tube within a tube structure of the body and how ectoderm covers the body surface, endoderm lines the hollow viscera and mesoderm is located in between.
Think about this for a moment. Ectoderm covers the outer surface of the body forming the epidermis of the skin with its appendages of hair and nails. The ectoderm also forms the nervous system, which sinks below the ectodermal surface, but which maintains connection to it through sensory neurons derived from neural crest ectoderm. Glands like the sweat glands that help regulate body temperature through evaporation or sebaceous glands that waterproof the skin with an oily secretion, and salivary glands are all outgrowths of the ectoderm.
Endoderm forms the epithelia that line the insides of the hollow viscera and is continuous with the skin at all body orifices. The ectoderm derived lining of the oral cavity transitions into the endoderm derived lining of the pharynx and the endoderm derived lining of the rectum transitions into the ectoderm derived lining of the anal canal. The endoderm layer that forms the linings of organs of the GI tract and the lungs, are modified to extract nutrients and oxygen from the environment.
Mesoderm forms the mechanical components of the body, that allow us to move about and interact with the environment. Muscles and skeleton for movement and heart and blood vessels to circulate blood that brings oxygen and nutrients to all of the body tissues. Smooth muscle to propel the contents of the hollow viscera through the body. Kidneys to extract toxins from the blood for excretion into the environment, gonads for reproduction.
In subsequent sections we will explore how the three embryonic tissue layers combine to form the functional components of each of the organ systems of the body.