Embryology of nervous system Flashcards
What are the prosencephalon and mesencephalon and rhombencephalon?
- Specializations along the rostro-caudal axis
- Development centers at the rostral end of the neural tube
- Primary cerebral vesicles
- Go on to develop into five secondary cerebral vesicles
How do each of the primary cerebral vesicles form the 5 secondary cerebral vesicles?
• Prosencephalic vesicle - segments from one into three
○ Telencephalic vesicles are paired vesicles cranially
○ They expand off of the more caudal diencephalic vesicle
• Mesencephalic vesicle - stays the same and does not further segment
• Rhombencephalic vesicle - splits into more cranial metencephalon and the more caudal myelencephalon
The secondary cerebral vesicles and their lumens correspond to what adult nervous system components?
• Telencephalic vesicles
○ These are paired and they form the cerebral hemispheres, each with a lateral ventricle
• Diencephalic vesicle
○ Thalamus, hypothalamus, subthalamus, epithalamus
○ Lumen of vesicle will give rise to third ventricle which communicates with each lateral ventricle through the foramina of monroe
• Mesencephalic vesicle
○ Mesencephalon (midbrain)
○ Lumen - aqueduct of sylvius
• Metencephalon
○ Pons and cerebellum
○ Lumen of rhombencephalon will become 4th ventricle which communicates with subarachnoid space
○ Paired foramina of Luschka and midline foramen of Magendie
• Myelencephalon
○ Medulla
○ Lumen of rhombencephalon will become 4th ventricle which communicates with subarachnoid space
○ Paired foramina of Luschka and midline foramen of Magendie
The lateral ventricles come from what?
• Lumen of telencephalic vesicles
What are the names of the 5 secondary brain vesicles?
- Telencephalon
- Diencephalon
- Mesencephalon
- Metencephalon
- myelencephalon
What is the initial event that appears to establish the axis of the embryo?
- Mammalian egg is symmetric, but sperm entry breaks symmetry
- Blastomere getting the sperm entry point tends to divide first forming the embryonic pole
- Rostrocaudal axis occurs with implantation, ICM side of blastocyst enters uterine wall
- The end that leads implantation is the caudal end
What are the early signalling events that helps the embryo grow along an axis?
- Signal from implanting trophoblast (nodal) induces a head organizer in the anterior hypoblast cell
- Secreted factor cerebrus inhibits nodal and creates a gradient of nodal signaling (rostrocaudal in orientation)
- Forms primitive knot, hensens node/primitive node
The primitive rod-like notochordal process is formed by what?
- Portions of the primitive mesoderm coalescing and forming the notocordal process
- This is just below the primitive node initially and grows caudally
- This structure is initially hollow
What is the “normal” destiny of the neurenteric canal?
- It normally regresses and the notochord coalesces into a solid tube
- However, this process and fail and cause a neurenteric fistula or neurenteric cyst
What is the neurenteric canal?
- The hollow notochordal process fuses with the endodermal layer
- As this fusion occurs there is a brief period of time where the amniotic cavity and yolk sac are in communication through the notochordal process
- The communication is called the neurenteric canal
The release of Sonic Hedgehog is due to what structure and what is the result?
- The notochord releases Shh
- Induces the overlying ectoderm to divide rapidly
- Forms a thickened cell mass called the neural plate
- Neural plate will then crease and form neural groove
- Eventually the groove will become a tube, which becomes the adult nervous system
What are the anterior and posterior neuropores?
- The small unroofed portions or openings at each end of the neural tube
- Part of the lengthening of the neural tube is when the neural folds come together in a “zipper like” fashion, progressing rostrocaudal toward each end
- The “zippering” doesn’t quite finish and that results in the two ends having neuropores
- The do eventually close as well
When does secondary neurulation take place?
- 28-32 days
- Aggregate of undifferentiated cells at caudal end of embryo (caudal cell mass) develops
- It develops vacuoles as it enlarges
- Ultimately makes contact with central canal of neural tube from primary neurulation
- Caudal cell mass gives rise to conus medullaris and filum terminale
What is a NTD less severe than a myelomeningocele but caused by the same general proces?
- Lack of a vertebral arch in a given area
- The neural tube does close but it is not completely surounded by the sclerotome
- The sclerotome makes up the vertebral arch, so that doesn’t form
- Usually there is a mark in the skin or a dimple where this lack of fusion took place
What went wrong if there is a myelomeningocele?
- Incomplete closure of the neural tube
* Plaque of neural tissue contiguous with epidermis
Where do the adult structures: conus medullaris and filum terminale come from in the embryo?
• The caudal cell mass of secondary neurulation
What might cause the failure of forebrain structures to develop?
- This is called anencephaly
- The neural tube does not close at the anterior neuropore
- The neuropores are the last areas in the “zippering” of the nerual tube to fully fold over and close
What dietary intervention has been key in reducing neural tube defects?
- Periconceptional folic acid supplements
- 400 micrograms of folic acid daily through the first trimester of pregnancy
- If they have previously had a NTD pregancy then 4mg daily 1 month before conception is recommended
What is a key molecular mechanism to determining an axis upon which the embryo devleops?
- A concentration gradient of morphogens secreted by anterior cells vs. posterior cells
- The concentration gradient gives rise to regional expression of different developmental control genes along the axis of the morphogen gradient
- Wnts, FGFs and retinoic acid are the major players for the AP/RC axis
What are the important morphogens for the development of the AP/RC axis?
- Wnts, FGFs and retinoic acid are the major players for the AP/RC axis
- Cerebrus and dickkopf are secreted by the anterior visceral endoderm and they promote forebrain differentiation
What factors, when secreted, promote forebrain differentiation?
• Cerebrus and dickkopf are secreted by the anterior visceral endoderm and they promote forebrain differentiation
*this is happening in the context of the RC/AP axis being developed in the embryo
What are the names of genes that are super fundamental in AP patterning of nervous tissue?
- Homeobox genes
- First discovered in Drosophila embryonic patterning
- Best characterized in development of rhombencephalon
What are rhombomeres?
- 8 morphologically distinct elements within the developing rhombencephalon
- They are repeating units that end up differentiating similarly, but distinct based on region
- Under the main control of homeobox genes
- Between rhombomeres, cells will differ in terms ofmorphology, axonal trajectories, NT synthesis, NT selectivity, firing properties and synapse specificity
What is the result of Hox gene expression varying along the AP axis of the neural tube?
- The result is a differential gene expression pattern overall in the different rhombomeres
- The programs of differentiation they trigger will vary according to position along axis
What is RA, and what are RAREs?
- RA is retinoic acid, a vital secreted factor for the deveolpment of the AP axis in neural development
- RA is membrane permeant and bindes to RARs or Retinoic acid receptors
- The receptors will invfluence gene expression along RA response elements in the DNA, or RAREs
- RA is highest in concentration around the posterior positions
- Too much RA means too much posterior structures at the expence of anterior ones
- Thus, RA can toxicity can mess up the embryo something fierce
What is the neuroepithelial layer?
- The walls of the neural tube initially possess a pseudostratified layer of primitive ectoderm known as the neuroepithelial layer
- Though uniform initially, it develops differently in the different RC sections
- This layer will eventually form nearly all of the cellular elements of the CNS
- Except for microglia which come from the reticuloendothelial system
What pattern of movement do the dividing cells within the neuroepithelial layer have?
- They oscillated between inner and outer walls
- The process of mitosis happens when they are near the inner wall
- They move back to the outer wall to start going through S phase
- The result is thickening of the walls of the neural tube and enlargements of vesicles at the anterior end
- Some will become neurons, others glial cells
In the neuroepithelial layer, what keeps the cells within the inner and outer walls?
- Cell bodies shift along their processes
- There are cell processess attached to the inner and outer walls and the cell bodies move out or in depending on what phase in the cell cycle they are
- Daughter cells can make their own processes OR they can lose them and end up being primed for migration
What’s up with the radial glial guide cells?
- As the walls of the neural tube are rapidly thickening, cells are moving between the inner and outer walls a lot
- Some of the glial cells form a rope ladder configuration along which primitive nerve cells can migrate
- Becomes necessary as the migration distance gets longer and longer
Where in the rapidly thickening walls of the neural tube is the growth the largest and the distance travelled the greatest?
- The telencephalon, which is becoming the cortex where most of the higher level of mental activity occurs
- It is made up of 6 cell layers and each layer is distinct in pattern of organization and connections
- Initially the cells migrate in and form the deepest, or 6th layer
- Each progressive migration forms a more superficial layer
- Think of an inside out sequence of devleopment where each new layer has to move through the deeper one
How is the “inside-out” migration scheme responsible for the different architecture of white vs. grey matter in the cortex vs. spinal cord?
- Unlike the spinal cord, where cells proliferate around the ventricular zone then send their axons out toards the periphery (grey matter centrally, white matter outward)
- The cells of the cortex migrate outwards, become established then send their axons and meyelin IN, forming a shell of grey matter and tracts of white matter diving deeper
Instead of the RC axis being super important, what axis seems to decide the fate of spinal cord neurons?
- The DV axis
- Those progentior cells closer to ventral aspect will become motor neurons
- Some of these will connect with the myotomes (thus innervate muscles)
- The progenitor cells in the dorsal regions will be sensory, receiving inputs from cells of the DRG (which themselves come from the neural crest)
What is the sulcus limitans?
- A crease in the neural tube in the developing spinal cord area
- Separates the ventral from dorsal population of neural progenitor cells
- Ventral - basal plate
- Dorsal - alar plate
What are the basal and alar plates?
- A crease in the neural tube in the developing spinal cord area
- Separates the ventral from dorsal population of neural progenitor cells
- Ventral - basal plate
- Dorsal - alar plate
What are the most important morphogens involved in dorsoventral patterning?
- Shh = sonic hedgehog (initially secreted by the notochord)
* BMPs - secreted by lateral ectoderm
What’s up with BMP signaling in the context of dorsoventral patterning?
- Initially BMP permeate the entire flat embryonic disc
- Secretion of BMP inhibitors by midline primitive node and notochord give rise to a BMP poor medial zone
- Thus pushing cells to commit to midline structures including the neural plate
- BMP rich lateral aspects make up the dorsal arch as the neural tube folds and zippers
- Shh and BMP spatial differences help establish dorsoventral axis
How is the cortex given its dorsoventral axis?
- Before the telencephalic vesicles begin to form, the rostral neural tube develops regionally restricted DV markers
- This creates three discrete proliferative zones
- Cortex - most dorsal
- Lateral and medial ganglionic eminences (in the middle)
- Basal forebrain - most ventral
What is the result of the telencephalic vesicle folding over itself?
• Formation of the sylvian fissure (lateral sulcus)
• Also buries a patch of cortex within the fissure producing the insular cortex
• The lateral ventricle associated with the telencephalic vesicle is distored into a C shape
• The caudate nucleus is also distorted into a C shape
○ Portion of the gray matter derived from the lateral ganglionic eminence
• The telencephalon structures follow the C shape, and coronal planes will cut through these structures twice
What are the putamen and globus pallidus?
- Separated structures by axons emanating from neurons in the cortex which are descending to multiple targets
- They are components of the basal ganglia
- The caudate nucleus is the medial basal ganglia structure
- These are from the telecephalon
The third ventricle comes from what?
• Diencephalic vesicle (lumen)
In what form does the nervous system begin?
- Flat epithelium called the neurectoderm
- This will round up and form the neural tube
- Formation of the neural tube marks the beginning of neurogenesis
When the ventricular walls are being developed (neurogenesis) where are the cell bodies of the precursor cells when they are in S phase?
- Most superficial, or furthest from the inner ventricular wall
- Cell division happens when the cell body is closest to the ventricle, or the inner wall
What are the regions in which proliferating cells are found? (neurogenesis)
- Ventricular zones that are the layer closes to the neural tube lumen/ventricle
- Or central canal in the case of the spinal cord
- Dividing cells have processes that attach medially to the ventriclular surface and laterally to the external surface (processes connecting them to the walls of the ventricle)
What is the method most used to study neurogenesis?
- Labeling dividing cells with detectable DNA precursors
- H3-thymidine or bromodeoxyuridine
- Cells take up labeled DNA building blocks during S phase
- A cell’s birthdate is defined as the time it undergoes its last round of DNA synthesis (S phase)
