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Cortical development


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Which derivative of the prosencephalon forms the rudiments of the cerebral cortex? When does the differentiation of the prosencephalon occur?
*between embryonic weeks 3 and 8
Describe the growth pattern that results in the hemispheric structure of the cortex.
*cells on the midline growth plate divide less and show more apoptosis...this results in the fixation of the plate
*cells in the lateral portions proliferate rapidly
Name one chemical secreted by organizer tissue that in part directs patterning of the cortex.
*sonic hedgehog (SHH)
Describe the gross defect seen in holoprosencephaly. Deletions in what gene have been implicated as a cause of HPE?
*forebrain fails to separate; cortex is continuous as a single holosphere rather than two hemispheres
*SHH in mesencephalon
In what part of the developing cortex does cell proliferation occur?
Ventricular zone of proliferation, adjacent to the lumen of the brain.
What kinds of cells are produced when a neural precursor cell divides symmetrically? When it divides asymmetrically?
*symmetric division = 2 glial cells
*assymetric division = 1 neuron + 1 glial cell
What are the signs of microcephaly? What is the general defect?
*small cortex, MR
*failure to generate the appropriate number of neurons
What is ASPM? What do defects in APSM result in? How?
*abnormal spindle protein
*interferes with the organization of spindle fibers in mitotic cells, causing them to arrest in M-phase
Mutations in the gene coding for B-catenin have caused what kinds of effects in lab animals? What is the mechanism?
*enlarged lateral ventricles and an expanded pool of neural precursors
When is neural cell fate atleast partially specified?
In the paraventricular zone when the neuron is born.
Underexpression of GABA neurons can be induced by a specific mutation - what is it?
Double mutations to D1x-1/2.
What is the difference between radial and tangential migration of neurons?
*radial migration: movement along a glial scaffolding system
*tangential migration: movement in a glial-independent manner
How are cortical layers laid out - inside-out or outside in?
Inside-out, with the deepest layers made first and the most superficial layers made last.
What are the 3 general stages in neuron migration?
1.Recognition of route and onset of migration
2.Maintenence of migration over long distances
3.Termination of migration at the proper location
What is schizencephaly?
*defect in neural migration results in random distribution of neurons
*fistula between ventricle and outer surface of brain seen
What is the gross appearance of the bain in Type 1 lissencephaly? What causes this defect? What is the mechanism?
*smooth cortical surface with no sulci or gyri
*mutation in Lis-1 gene
*abnormal accumulation of microtubules
What is the appearance of periventricular hetertopia? What is the primary problem? What symptoms are seen?
*enlarged periventricular area
*failure of neurons to initiate migration
What is the molecular problem in periventricular hetertopia?
Mutations in the gene coding for filamin-1 prevent f-actin filaments from binding together normally.
Is periventricular hetertopia seen more frequently in boys or girls?
It is not seen in boys. The mutation is on an X-linked gene and males are spontaneously aborted. Females survive because they are mosaic carriers.
What is the appearance of polymicrogyria?
Small gyri inside the cortex.
a-3 integrin is proposed to play what role in neural migration? What is the molecular defect seen in knockout animals?
*recognition of surroundings during migration
*disruption of f-actin dynamics at the leading edge
Reeler mouse mutants have neurons that show an inability to terminate migration at the appropriate location. What is the appearance of these animals' brains?
The laminar structure of the cortex is reversed with layer 6 most superficial and layer 1 most deep.
How is neural migration affected in Walker-Warburg syndrome? What anatomical anomalies are seen?
*neurons fail to terminate migration at the proper location and splay out through the pia mater into the subarachnoid space
*hydrocephaly, thinning of the cortex, aplasia of corpus callosum
What is the genetic defect thought to be the cause of Walker-Warburg syndrome?
A mutation in the gene coding for mannosyltransferase wich regulates the glycosylation of many proteins.
What are the 6 steps in normal cortical development?
1.Pattern formation
2.Cell proliferation
3.Cell fate specification
4.Cell migration
5.Cell differentiation
6.Synapse and circuit formation
A failure to make the correct synaptic connections generally results in what?
Induction of apoptotic pathways.
What defect results in neurological separation of the two cortical hemispheres?
Agenesis of the corpus callosum.
What is tuberus sclerosis? What is a common symptom?
*groups of abnormally placed neurons (tubers) make abberent connections with a variety of effects
Fragile X Syndrome results from a mutation in the FMR-1 gene. What are the roles of this gene in normal individuals? There are three.
1.Influence the initial generation of a synapse
2.Regulate the generation of NT's and chemotactic factors at the synapse
3.Destroy RNA complexes
How does the mutation of FMR-1 seen in Fragile X affect transcription of the gene?
*increases the number of CCG repeats in the gene
*this induces methylation of the gene
*transcription is turned off
What structural anomalies are seen in Fragile X syndrome?
*increase in dendritic spine density
*excess of long, thin spines
ARFGEF2 codes for proteins normally involved in vesicular transport of membrane components. What 2 defects are seen when this gene is mutated? What protein is inadequately transported in these patients?
1.periventricular hetertopia
What are three general effects seen in FAS?
1.Increased neuronal apoptosis
2.Sparsity of dendrites
3.Deficits in neuronal growth resulting in loss of brain surface morphology
Describe microdysgenesia of the cortex. In what genetic condition is it commonly seen?
*abnormal gyrations that protrude through to subcortical layers
*trisomy 21
The brains of autistic patients are commonly much smaller in volume than normal brains.
False: most autistic patients exhibit macrocephaly.
Mutations in the neuregulin-1 gene have been implicated in schizophrenia. What is the normal role of this gene?
Development of radial glial cells and expression of certain neurotransmitter receptors.
Cortical development continues into adulthood.
This is true.

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