1 - Central Nervous System Development Flashcards by Jason Yin

Gastrulation

i. Epiblast cells ingress through primitive streak by undergoing epithelial to mesenchymal transition
ii. Migrating cells displace hypoblast cells, these displaced hypoblast cells become definitive endoderm which eventually become the gut tube
iii. A second layer of ingressing epiblast cells forming between epiblast and endoderm are definitive mesoderm cells
iv. Once gastrulation is complete, epiblast cells are now termed the ectoderm
v. Gastrulation, or formation of three germ layers, produces the “trilaminar disk”

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Formation of Notochord

i. The primitive streak will regress caudally following gastrulation (Day 17)
ii. The notochord (axial mesoderm) extends cranially as the streak regresses
iii. The notochord goes through significant and complex remodeling including differentiation from a tube into a solid rod and eventually becoming the nucleus polposus in adults

“Caudally” is a term used in anatomy and biology to refer to a position or direction toward the tail or posterior end of an organism. It is the opposite of “rostrally,” which indicates a position or direction toward the head or anterior end.

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Neurulation - beginning

iv. Around D18, the primitive node stimulates the ectoderm to thicken (neural plate)
v. The neural plate bends around on itself forming a neural groove and eventually closes (neural tube)
vi. Fusion of the neural folds proceeds in cranial and caudal directions until only small areas of neural tube are open at each end (anterior and posterior neuropore)
vii. This process is highly regulated by several signaling morphogens: Shh (notochord), Fgf (paraxial mesoderm), Wnt and Bmp (overlying ectoderm)

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Neurulation: Formation of the Nervous System

viii. The neural tube differentiates into the brain and spinal cord (CNS)
ix. Neural crest cells delaminate off dorsal neural tube during closure and migrate to the developing embryo differentiating into a variety of
different cell types including but not limited to:
1. peripheral nervous system
2. adrenal medulla
3. portions of the outflow tract of the heart
4. pharyngeal arch cartilages
5. components of the cranial nerve ganglia
6. stromal and smooth muscle tissues of the eyes
7. melanocytes

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Fusion of the Neural Folds: Brain and spinal cord

Improper closure of the neural tube

Anterior neuropore – defects in anterior neuropore closure (Day 24) may also result in disrupted of brain development
i. Anencephaly/Meroencephaly (absence of major portion of brain and skull)
ii. Encephalocele (cranium bifidum) (defect in skull formation – can include brain meninges or both)
1. Cranialmeningocele (meninges)
2. Meningoencephalocele (brain and meninges)
3. Meningohydroencephalocele (brain, meninges and ventricle)

iii. Cranioachischsis (complete failure of neural tube closure)

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Improper closure of the neural tube:
Posterior neuropore

Posterior neuropore – defects in closure of the posterior neuropore (Day 28) are
accompanied by anomalies of the vertebral arches. These malformations, called spina bifida, vary in severity depending on the degree to which the spinal cord protrudes through the open vertebrae and skin.

i. Spina bifida occulta (vertebral arch defect)
ii. Meningocele (protrusion of meninges and CSF)
iii. Myelomenigocele (protrusion of meninges, CSF and neural tissue)
iv. Myeloschisis (open spinal cord)

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causes and screening for neural tube defects

C. Elevated alpha-fetoprotein levels indicate potential neural tube defect (Except in spina bifida occulta). Confirmation with amniocentesis. Ultrasound imaging might also reveal gross abnormalities.
D. Folate antagonists (methotrexate and valproic acid) are highly teratogenic and can cause
NTDs. Other teratogens include: phenytoin, retinoic acid, maternal diabetes and TORCHeS

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Cytodifferentiation/Histogenesis of the neural tube

A. The neural tube caudal to the fourth pair of somites develops into the spinal cord
B. The lateral walls of the neural tube thicken and gradually reduce the size of the neural canal to a minute central canal
C. Initially, the wall of the neural tube is composed of a thick, pseudostratified, columnar neuroepithelium. These neuroepithelial cells constitute the ventricular zone (ependymal layer), which gives rise to all neurons and macroglial cells (macroglia) in the spinal cord.
D. Some dividing neuroepithelial cells in the ventricular zone differentiate into primordial
neurons→neuroblasts which form an intermediate zone (mantle layer) between the ventricular and marginal zones. Neuroblasts become neurons as they develop cytoplasmic processes. Glioblasts (supporting cells of the CNS) differentiate from neuroepithelial cells and migrate into intermediate and mantle zones. The mantle layer forms the presumptive grey matter of the spinal cord
E. When neuroepithelial cells cease producing neuroblasts and glioblasts, they differentiate into ependymal cells, which form the ependyma (ependymal epithelium) lining the central canal of the spinal cord
F. Soon a marginal zone composed of the outer parts of the neuroepithelial cells is recognizable. This zone gradually becomes the white matter of the spinal cord as axons grow into it from nerve cell bodies in the spinal cord, spinal ganglia, and brain.
G. Further proliferation of the neuroepithelial cells alters neural tube shape as a roof plate, floor plate and sulcus limitans are now identifiable

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Regionalization of neural tube

BMPs and Sonic Hedgehog signaling establish dorsal-ventral gradients in the neural tube that affect cell differentiation.
i. The dorsal and ventral regions of the neural tube become the alar and basal plates, respectively. The plates are demarcated by the sulcus limitans.
ii. The alar plate functions in the transmission of sensory information (afferents) while the basal plate contains neurons that regulate motor activity (efferents). These anatomical and functional regions are present in the spinal cord and extend into the brain.

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Development of meninges and growth of spinal cord

i. The meninges (membranous covering of the brain and spinal cord) develop from
cells of the mesenchyme and neural crest cells during days 20 to 35. These cells migrate to surround the neural tube (primordium of brain and spinal cord) and form the primordial meninges. The external layer of these membranes thickens to form the dura mater. The internal layer—the pia mater and arachnoid mater (leptomeninges) —is derived from neural crest cells. Fluid-filled spaces appear within the leptomeninges that soon coalesce to form the subarachnoid space. Cerebrospinal fluid (CSF) begins to form during the fifth week.

J. Positional changes of the spinal cord
i. The vertebral column grows faster than the spinal cord. Nerves that extend past the
end of the spinal cord (medullary cone) are surrounded by meninges in the cauda equina. Distal to the caudal end of the spinal cord, the pia mater forms a long, fibrous thread, the filum terminale (terminal filum), which indicates the original level of the caudal end of the embryonic spinal cord.

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Brain Formation

A. The brain begins to develop in the third week when the neural plate and tube are developing from neuroectoderm
B. The neural tube, cranial to the fourth pair of somites, develops into the brain. Neural
progenitor cells proliferate, migrate, and differentiate to form specific areas of the brain. Even before the neural folds are completely fused, three distinct primary brain vesicles are recognizable in the rostral end of the developing neural tube. From cranial to caudal, these primary brain vesicles form the forebrain (prosencephalon), midbrain (mesencephalon), and hindbrain (rhombencephalon).
C. During the fifth week, the forebrain partly divides into two secondary brain vesicles —the telencephalon and diencephalon; the midbrain does not divide. The hindbrain partly divides into two vesicles, the metencephalon and myelencephalon. Consequently, there are five secondary brain vesicles.
D. The cranial part of the forebrain is the telencephalon which forms the cerebral hemispheres. The caudal (posterior) part of the forebrain is the diencephalon. The cavities of the telencephalon and diencephalon contribute to the formation of the third ventricle.
E. The embryonic brain grows rapidly during the fourth week and bends ventrally with the head fold. The bending produces the midbrain flexure in the midbrain region and the cervical flexure at the junction of the hindbrain and spinal cord. Later, unequal growth of these flexures produces the pontine flexure in the opposite direction. This flexure results in thinning of the roof of the hindbrain and ventrolateral displacement of the sulcus limitans, alar and basal plates.

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Rhombencephalon (hindbrain) formation
i. Myelencephalon (most posterior/caudal portion) → medulla

Myelencephalon → medulla
1. As the basal and alar plates move ventrolaterally due to the pontine flexure, the motor nuclei will develop medial to the sensory nuclei
2. Neuroblasts of the basal plates of the medulla form the motor neurons which organize into three cell columns
a. General somatic efferent → neurons of hypoglossal nerve (innervates tongue)
b. Special visceral efferent → neurons innervating pharyngeal arches
c. General visceral efferent → neurons of Vagus and Glossopharyngeal nerve
3. Neuroblasts of the alar plates of the medulla form the sensory neurons which organize into four cell columns
a. General visceral afferent → receive impulse from viscera
b. Special visceral afferent → receive taste fibers
c. General somatic afferent → receive impulse from surface of head
d. Special somatic afferent → receive impulse from ear
4. Some neuroblasts from the alar plates migrate ventrally and form the neurons in the olivary nuclei

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Rhombencephalon (hindbrain) formation:
Metencephalon (ventral portion of hindbrain): Pons and Cerebellum

Metencephalon → pons and cerebellum
1. The pons develops as a protrusion in the ventral aspect of the metencephalon
2. The cerebellum develops dorsally from a proliferation of cells in the rhombic lip adjacent to the fourth ventricle. Fissures and folia form in the cerebellum.
3. The choroid plexus consists of ependymal cells and capillaries present in the pia layer that project into the roof of the fourth ventricle.
4. Herniation of the caudal brainstem and cerebellum through the foramen magnum is called an Arnold-Chiari malformation. This may affect the flow of cerebral spinal fluid (CSF) and lead to hydrocephalus.

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Development of Mesencephalon
Midbrain

Mesencephalon (Midbrain formation)
i. The neural canal (containing CSF) narrows forming the cerebral aqueduct which connects the third and fourth ventricles
ii. Proliferation of neuroblasts in the dorsal mesencephalon (alar plate) gives rise to the superior and inferior colliculi that are involved in vision and audition, respectively.
iii. The basal plate (motor nuclei) gives rise to the red nucleus and the substantia nigra.

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Prosencephalon (Forebrain formation):
Diencephalon (posterior portion of Prosencephalon) → thalamus, hypothalamus, epithalamus, pineal gland, posterior pituitary

Three swellings develop in the lateral walls of the third ventricle, which later become the thalamus, hypothalamus, and epithalamus
-The thalamus develops rapidly on each side and bulges into the cavity of the third ventricle, eventually reducing it to a narrow cleft.
-The hypothalamus arises by the proliferation of neuroblasts in the intermediate zone of the diencephalic walls.
-The epithalamus develops from the roof and dorsal part of the lateral wall of the diencephalon. Initially, the epithalamic swellings are large, but later they become relatively small
The pineal gland develops as a median diverticulum of the caudal part of the roof of the diencephalon. Proliferation of the cells in its walls soon converts it into a solid, cone-shaped gland.
The pituitary gland (hypophysis) is ectodermal in origin. It develops from two sources:
a. An upgrowth from the ectodermal roof of the stomodeum—the hypophyseal diverticulum (Rathke pouch) → Anterior pituitary(adenohypophysis)
b. A downgrowth from the neuroectoderm of the diencephalon—the neurohypophyseal diverticulum → Posterior pituitary
(neurohypophysis)
c. This double embryonic origin of the pituitary gland explains why it is composed of two different types of tissue

“diverticulum” is a medical term that refers to a small pouch or sac that can form in the lining of various organs in the body

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Prosencephalon (Forebrain formation):
Development of Telencephalon (anterior portion of prosencephalon) → Cerebral hemispheres

The telencephalon consists of a median part and two lateral diverticula, the cerebral vesicles. These vesicles are the primordia of the cerebral hemispheres
The cavity of the median part of the
telencephalon forms the extreme anterior part
of the third ventricle.
At first, the cerebral hemispheres are in wide communication with the cavity of the third ventricle through the interventricular foramen
As the cerebral hemispheres expand, they
cover successively the diencephalon,
midbrain, and hindbrain. The hemispheres
eventually meet each other in the midline, flattening their medial surfaces.
The cerebral hemispheres grow within a confined space. This creates fissures and gyri that increase in number and prominence throughout development.
The longitudinal fissure lies between the cerebral hemispheres. Absence of this fissure results in holoprosencephal:
a. Failure of left and right hemispheres to separate; usually occurs during weeks 5–6.
b. Literature suggests potential association with sonic hedgehog signaling pathway as cyclopia is observed together with holoprosencephaly
c. Also associated with Patau syndrome and fetal alcohol syndrome

distinction between positioning terminology

Anterior/Posterior:
Anterior: Toward the front or head end.
Posterior: Toward the back or tail end.
Example: The frontal lobe of the brain is anterior to the occipital lobe.
Rostral/Caudal:
Rostral: Toward the front or nose end (used specifically in the brain).
Caudal: Toward the back or tail end (used specifically in the brain).
Example: The rostral part of the brainstem is involved in higher-order functions, while the caudal part is involved in more basic functions like breathing.
Ventral/Dorsal:
Ventral: Toward the front or belly side.
Dorsal: Toward the back or upper side.
Example: The spinal cord is dorsal to the heart.
Superior/Inferior:
Superior: Higher or above.
Inferior: Lower or below.
Example: The superior colliculus in the midbrain is involved in visual processing.
Medial/Lateral:
Medial: Toward the midline or center.
Lateral: Away from the midline or toward the sides.
Example: The medial temporal lobe is involved in memory, while the lateral frontal lobe is involved in executive functions.

Anterior: The front door of the house. In brain anatomy, this is a general term indicating the front or head end of a structure.
Example: The frontal lobe of the brain is like the front part of the house, facing forward.
Rostral: Now, let’s imagine the house has a long, narrow front yard extending from the front door towards the street. The “rostral” part would be the farthest point of that front yard.
Example: In brain anatomy, the rostral part is specific to the brain and refers to structures toward the front or nose end.
Ventral/Dorsal: Now, let’s imagine the house has a basement and an attic.
Ventral: The basement of the house, below the ground level.
Dorsal: The attic of the house, above the ground level.
Example: In brain anatomy, the spinal cord is like the basement (ventral) because it’s located toward the belly side, and the superior colliculus is like the attic (dorsal) because it’s located toward the upper side.

diagram of Prosencephalon (forebrain), Mesencephalon (midbrain), Rhombencephalon (hindbrain) and their components

Development of the ventricles

A. The ventricular system is a set of four interconnected cavities (ventricles) in the brain, where the cerebrospinal fluid (CSF) is produced by a network of ependymal cells (choroid plexus)

B. Ventricular system
i. Telencephalon → lateral ventricles (2)
ii. Diencephalon → 3rd ventricle
iii. Mesencephalon → cerebral aqueduct
iv. Metencephalon → 4th ventricle
v. Myelencephalon → 4th ventricle

C. Abnormalities associated with the brain ventricles
i. Hydrocephalus
1. Impaired circulation and absorption of CSF or, in unusual cases, from increased production of CSF → increased CSF present in brain ventricles
2. An infant with hydrocephalus has a significant enlargement of the head and atrophy of cerebral cortex and white matter
3. Impaired circulation of CSF often results from congenital aqueductal stenosis (narrow cerebral aqueduct)
ii. Chiari Malformations
1. Displacement of cerebellum through the foramen magnum into the vertebral canal resulting in blockage of CSF and hydrocephalus
2. Can be congenital or caused by trauma

Development of Eyes (Diencephalon)

A. The eyes develop from the optic sulci in the lateral walls of the diencephalon (DAY 21)
before anterior neuropore closes
B. The sulci enlarge to form the optic vesicles that are connected to the forebrain via the optic stalks
C. Ocular structures form as a result of a series of inductive interactions mediated by several families of signaling molecules. The optic cup signals to the overlying ectoderm to form the lens placode which invaginates to form the lens vesicle. The lens induces the development of the overlying cornea.
D. The optic vesicles fold in on themselves to form the optic cups. The innermost layer (closest to the developing lens) gives rise to the neural retina containing the photoreceptors and other neurons that transmit visual information to the optic nerve. The outermost layer (closest to the brain) forms the retinal pigmented epithelium which is associated with the vascular choroid. The space between the two layers closes but remains vulnerable to detachment.
E. The hyaloid artery grows into the eye through the retinal fissure (optic fissure/choroidal fissure – all same thing) which closes to encase the artery. The distal portion of the hyaloid artery that supplies the lens degenerates. The remaining segment of the hyaloid artery becomes the central artery of the retina that supplies a portion of the neural retina and optic nerve. The photoreceptor layer does not have its own blood supply and is dependent on blood vessels in the choroid for nutrients and oxygen.
F. Congenital eye defects result from mutations in transcription factors, abnormal signaling pathways, infection, etc. that affect the size and location of the eyes, differentiation of ocular structures, transparency of the lens, fusion of the neural and pigmented retinal layers, and closure of the retinal fissure.
i. Retinal detachment = incomplete fusion of inner and outer layers of optic cup
ii. Coloboma = incomplete fusion of retinal fissure (optic fissure)
iii. Congenital glaucoma= abnormal development of scleral venous sinus causing intraocular tension (correlated with rubella infection)
iv. Congenital cataracts = abnormal development of lens (correlated with rubella infection)