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Cns Development Notes

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Bavidra Kulendrarajah CNS development notes: Intro
- nervous system is made of two components:
-CNS: brain and the spinal cord
-peripheral nervous system: neurons and glia lying outside the central nervous system.
- experimental models have allowed us to understand the embryonic origins of the nervous system, key genes and mechanisms involved in its development.
-inducing pathological changes in the development of the nervous system in animal models and analysing defects in humans, it has allowed for further understanding and possible treatment of neurodevelopmental defects
- formation of the nervous system begins with neurulation, which involves the formation and the folding of the neural plate.
-followed by morphological changes in the tube to form the spinal cord and the brain. During this, neurons and glia begin to develop either from within the neural tube or from neural crest cells. Development of the CNS Neuralation: i) Neural induction
-Development of the future CNS starts on day 18 with the primitive node (organiser) Node induces the ectodermal cells to differentiate into pseudo stratified neuroectodermal cells.
-default fate of the ectoderm is to become the epidermis which is caused by signalling molecules BMP4 released laterally from the mesoderm.
-But BMP4 signals are medially inhibited by antagonists such as Noggin, Chordin, Nodal and Follistatin which are secreted from the primitive node.
-antagonists bind to BMP4 in the extracellular space and prevent it from binding to its receptors on the ectodermal cells.
-results in the induction of the neural plate medially.
-Another signalling molecule found to play a key role in neural induction is FGF8 which results in the formation of the posterior neural plate. This was shown as a knockout of FGF8 gene resulted in the formation of a structure similar to the anterior neural plate.
-Key role played by the primitive node in the formation of the neural plate was shown by Spermann and Mangold in 1924.
-When the dorsal lip, which acts as the organiser, was transplanted from the dorsal side of the non-pigmented blastopore to the ventral side of another pigmented embryo it resulted in the formation of 2nd body axis that contained a neural tube.
-Extra neural tube was pigmented and developed from the ectoderm which would have otherwise assumed an epidermal fate.

Bavidra Kulendrarajah
-This showed that the formation of the 2 nd neural tube is dependent on the original blastopore with the implanted node only providing signals for its formation.

ii) Change in shape of neural plate Once neural induction has occurred, the next stage is the change in shape of the neural plate.
-At cranial end, the neural plate is broader whilst caudally the plate begins to narrow and rapidly elongate.
-Narrowing and rapid elongation of the tube is known as convergent extension
-Experimentally shown to occur in Xenopus using dye.
-In an experiment carried out by Schectman and Holfreter it was shown that when dorsal tissue was removed from the embryo and cultured in isolation, the tissue narrowed and elongated in a perpendicular axis to the plane of the explant.
-showed that the motive force was generated intrinsically within the tissue and it was caused by a rearrangement of cells and not cell elongation.
- Key signalling molecules involved in convergent extension are Wnt ligands which induce the planar cell polarity pathway to result in changes in cytoskeletal activity. iii) Bending of the neural plate
-bending of the neural plate to form the neural tube starts at around day 22 and ends with it being invaginated into the mesoderm.
- Key to this process is the formation of hinge points which are regions where the neuroepithelial cells change from being columnar to wedge shaped and become attached to an adjacent structure through deposition of extracellular matrix material.
-2 types of hinge points: median and dorsolateral.
-Median hinge point: neuroepithelial cells are attached to the underlying notochord, which also induces changes in the shape of these cells.
-Role of the notochord in bending was shown by Smith and Schowewolf in 1989 who used notochordless chick embryos.
-Resulted in the midline neuroepithelial cells failing to develop the characteristic wedge shape which led to the absence of a median hinge point.
-Whilst neural plate bending still occurred, the neural tube had an abnormal morphology.
-When isolated segments of quail notochord were transplanted near the lateral epithelial areas of chick, cells changed from being tall and spindle shaped to being wedge shaped and became attached to the notochord.

Bavidra Kulendrarajah
-Dorsolateral hinge points: form at the cranial region of the neural plate which is much broader and the cells involved in these hinge points attach to adjacent surface ectoderm. iv) Formation of the neural groove and neural tube
-Once the hinge points form, neural folds made of both neuroepithelium and adjacent surface ectoderm elevate dorsally and rotate around these points to form the neural groove.
-Closure of the neural groove occurs with the fusion of the neural folds and begins at the future occipital and cervical regions.
-From this region, closure proceeds cranially and caudally with the closure of the cranial and caudal neuropores happening on days 24 and 26 respectively.
-This results in the formation of the neural tube with a space known as the central canal.
-After closure occurs, cells within the folds are rearranged to form two separate epithelial layers; the roof plate of the neural tube and the overlying surface ectoderm.
-At the interface between these 2 epithelial are the neural crest cells which form from epithelial to mesenchymal transformation of cells in the neural folds.
-The notochord also plays an important role in the formation of neural crest cells as it produces a ventral to dorsal concentration gradient of BMP4 antagonist chordin. The high concentration of BMP4 dorsally leads to EMT. Neural tube defects
-Clinical problems that arise from neurulation are known as neural tube defects, which can be open to the surface or covered with skin.
-Open neural tube defects, known as dysraphisms, are more severe
- total dysraphism known as craniorachischisis: neural tube is completely open to the surface
-localised dysraphism such as lumbosacral myeloschisis/ spina bifida aperata: lowermost region of spinal cord is open to the body surface.
-Spina bifida aperta can be classified as
-meylomeningocele-neural tube +
arachnoid) protrude from the canal




- meningocele which is when only the membranes protrude.
-Dysraphism in the brain is known as cranioschisis or anencephaly and infants who have this often have an absent forebrain.
-skin covered neural tube defects are less severe.
-Spina bifida occulta- defect is hidden but location is marked on the skin either by a tuft of hair/ angioma/ dimple.
-Skin covered neural defects occurring in the brain  encephaloceles  seen when brain tissue protrudes through the skull.

Bavidra Kulendrarajah
-neural tube defects are often diagnosed by measuring the alpha protein in maternal serum at 12 weeks of gestation and elevated levels often symbolise a defect.
-Some possible causes have been identified such as folate acid/vitamin B9 deficiency. This is shown as when pregnant women take 400micrograms it reduces neural tube defects by up to 75%. Consequences
-Myelomeningocele- spinal nerves fail to develop normally- dysfunction of pelvic organs and lower limbs
-People also suffer from Arnold Chiari malformation- hydrocephalus- normal drainage of CSF from the brain ventricles to subarachnoid space is disrupted
-Treated: implanting a shunt, unidirectional flow valve into lateral ventriclesallows fluid to drain into a body cavity
-Tethered spinal cord: lower end of spinal cord attached to skin- as child grows, vertebral column elongates-restricted cord elongates-neurological deficit Causes
-Some genetic predisposition: 1 baby then recurrence is 1 in 40, 2 babies 1 in 20
-Teratogenic: Experimental studies- retinoic acid, insulin and high plasma glucose lead to formation of NTD, also shown induction of NTD- antiepileptic dug- valproic acid, maternal diabetes, hyperthermia
-Folate acid- vitamin B9- 400micrograms- reduce NTDs by up to 75%
Morphological changes in the neural tube
-As the bending of the neural plate occurs, morphological changes in the cranial region of the neural plate begin to occur.
-First noticeable change is the appearance of 3 major divisions, known as primary brain vesicles in the cranial region of the neural plate.
-These consist of the prosencephalon, mesencephalon and the rhombencephalon which go on to differentiate as the forebrain, midbrain and the hindbrain respectively.
-With the closure of the neural tube, the 3 primary brain vesicles then subdivide into 5 secondary brain vesicles Differentiation of the fore brain
- forebrain which plays an important role in conscious awareness, cognition and voluntary action, develops from the prosencephalon.
-Prosencephalon sprouts of a pair of optic and telencephalic vesicles.
-Unpaired structure that remains after the formation of secondary vesicles is known as the diencephalon.
-Optic vesicles grow and invaginate to form optic stalks and cups.

Bavidra Kulendrarajah
-Optic stalks: Portion of tissue that provides a pathway for axon migration from the retina. The cells of the optic stalk later differentiate into glial cells of the optic nerve
-The optic cups become divided into an inner layer which forms the pigmented epithelium and the outer layer which forms the retina.
-These two layers eventually make contact with the surface ectoderm. As the eye is an outgrowth of the brain, where there is papilledemawe see raised intracranial pressure
-Telencephalic vesicles give rise to 2 cerebral hemispheres which grow posteriorly so that they lie over and lateral to the diencephalon.
-ventral medial surfaces of the hemispheres then become fused with the lateral surfaces of the diencephalon and this forms the basal ganglia.
-Caudal end of each hemisphere curves ventrally, grows forward to form the temporal lobe and the region of the cortex that is covered by this lobe is known as the insula. 2) Another pair of vesicles sprout off the ventral surface of cerebral hemispheres to give rise to the olfactory bulbs-sense of smell Kallmann syndrome: anosmiaolfactory bulbs and nerves fail to develop. Hypogonadism occurs as it fails to produce GnRH. GnRH neurons originate in olfactory placodes and migrate to the hypothalamus
-End of 6th month, continued proliferation causes the hemispheres which are initially smooth surfaced to become folded into a complex pattern of gyri and sulci and these separate the different lobes of the forebrain.
-The neurons in the cerebral hemispheres form two different types of grey matter;
-Cerebral cortex, made of collections of cell bodies on the outer layer of the hemisphere
-Basal ganglia, made of collection of cell bodies on the floor of the telecephalon.
-axons of these neurons form three major white matter tracts; cortical white matter (axons run to and from neurons in cerebral cortex), corpus callosum (continuous with cortical white matter and forms axonal bridge that links cortical neurons of 2 cerebral hemispheres) and the internal capsule (links cortical white matter with brain stem)
-Diencephalon subdivides into 3 subdivisions known as the neuromeres.
-Rostral neuromeres develop into the hypothalamus which plays an important role in regulating the endocrine activity of the pituitary and is also part of the limbic system which controls emotion.
-middle neuromere forms the thalamus and the epithalamus.
-caudal neuromere forms the pretectum. Differentiation of the Midbrain
-midbrain acts as a conduit for information passing from the spinal cord to the forebrain and develops from the mesencephalon.

Bavidra Kulendrarajah
-dorsal surface of the mesencephalic vesicles becomes the tectum whilst the floor gives rise to the tegmentum.
-The tectum differentiates into two structures:
-superior colliculus receives direct input from the eye, plays a role in controlling orientation of the eyes and the head
-Inferior collicus receives sensory information from the ear and contains two nuclei which transmit information to the auditory areas of the cerebral hemispheres.
-The tegmentum is made up of 2 cell groups- both of which are involved in voluntary movement.
-substantia nigra
- red nucleus Differentiation of the Hindbrain
-hind brain: cerebellum, pons and the medulla oblongata  plays an important role in the processing sensory information, control of voluntary movement and regulation of ANS.
-develops from the rhombecephalon which like the diencephalon also divides into 7/8 swelling known as rhomobomeres.
-rhombomeres are then segregated into metencephalon and the myelencephalon.






a) Cerebellum
-important movement control centre originates from rhombomeres 1 and 2, also known as the metencephalon.
-formed from the fusion of the rhombic lips which originate from the dorsal lateral wall of the neural tube in the region of the hind brain.
-then becomes separated into cranial cerebellar flocculondular lobes by a transverse groove.




-The embryonic origin of the cerebellum was shown by scientists who used lineage tracing involving genes En1 and En2, both found in the hindbrain region.
-cerebellum contains two types of grey matter
-deep cerebellar nuclei + external cerebellar cortex.
- malformations of the cerebellum  ataxia where people have problems with balance and coordinating movements.
-An example is Gillespie syndrome, which is caused by mutations in PAX 6 gene and this leads to hypoplasia of the cerebellum. b) Pons
-develops from the swelling of the ventral wall of the metencephalon.
-Important role in relaying signals that link both the spinal cord and the cerebral cortex, contains massive axon tracts.

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