HTHSCI 1DT3 Quiz: Module 1 - Summaries.8
23 Jun 2018
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Compare and contrast the development of the laminar structure of the neocortex and cerebellar
cortex, with a particular focus on molecular guidance and migration of cells.
Introduction
Embryonic development of the central nervous system is a highly complex and regulated
procedure, which involves several inductive and inhibitory cues to ensure the development
of the correct cells in the appropriate places.
Variety of signalling pathways enables development/neurogenesis and proliferation of
neurones that develop the cerebral cortex and cerebellum.
Cortex - higher functions, cognition, initiating movement, processing sensory stimuli
Cerebellum – works in sensing posture, balance and coordination, and generates patterns of
muscle changes needed for movement. Also learns timing and sequence needed for new
situations. Essentially judges errors between intended and actual voluntary movements –
adjusts motor pattern accordingly.
Also now thought to have a role in cognition (e.g. linguistic, executive and visuospatial, as
shown in cerebellar cognitive affective syndrome)=
Hoshi (2005) showed using Rabies (which spreads via synapses) that cerebellum connects
to basal ganglia.
Cerebral Cortex and Cerebellar Cortex Structure
Cerebral Cortex - 6 layered structure (Layer I – superficial, Layer VI – deepest)
Different layers have different functional orientations (e.g. primary motor cortex has greater
number of cells in Layer V/output layer)
80% are excitatory projection (pyramidal) neurons
Problems in the ‘wiring’ of the cerebral cortex (misfiring) is clinical basis of epilepsy.
Cerebellum divided into cerebellar cortex and cerebellar white matter (containing deep
cerebellar nuclei).
Cerebellar cortex – 3 layered structure (Molecular Layer, Single-Cell Purkinje Cell Layer,
Granular Layer)
Cerebral and Cerebellar Cortex Development
Development of the central nervous system occurs through neuralation (folding neural tube),
inhibition of BMP4/Wnt by noggin, chordin, cerebrus and follistatin, permit proneural genes
to occur.
Cortical projection neurons develop from neuroepithelium (ventricular / subventricular
zones). Importance of Retinoic Acid (RA) in patterning neuroepithelium.
Three Phases of Cerebral Cortical Development – (Inside Out Development)
Expansion Phase – symmetric division of neuroepithelium to form daughter neural
precursor cells.
Neurogenic Phase – Environmental signals (Notch, ErbB, Nrg1, FGF10, RA) stops
symmetric division, drives asymmetric division (formation of neuronal progenitor and
neuron daughter cells).
Neuron daughter cells formed (with stimulation from proneural genes)
Radial glia daughter cells formed shortly after – span ventricular to pial surface, act
as a guide for neuronal migration.
Interkinetic Nuclear Migration – neuronal nuclei within progenitor cells move during
cell cycle Del Bene (2008) - Regulates amount of Notch signalling neuronal
precursors received.
High notch concentrations at the apical side near nuclei – promotes division
of progenitors.
Low notch concentrations near nuclei – permits differentiation to neurons and
later glia.
Neurogenic Phase - cortical development begins at telencephalic wall (starts one cell
thick), which undergoes rapid cell division – ‘Inside-Out Development’ / radial
migration.
Developing cortex can be split into: Marginal zone, cortical zone, intermediate zone
and ventricular zone.
Migration of neurones occurs from the ventricular surface along radial glia towards
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Migration of neurones occurs from the ventricular surface along radial glia towards
pial surface.
Successive waves of neurones migrate on top of previously migrated neurones to
form the inside-out development scheme.
Thought to be mediated by reelin produced by Cajal Retzius cells at pial surface, and
attracts neurons towards pial surface. Important in both cerebral and cerebellar
development – role in cerebellar development discussed later.
Tangential Migration – While most neurones in cerebral cortex develop by radial
migration, some migrate by tangential migration (i.e. from far away – GABA stellate
cells from lateral ganglionic eminence).
Gliogenic Phase – switch transforms radial glia to differentiate into astrocytes: found to be
mediated by DNA methylation changes that normally block binding of STAT3 (‘hides’ glial
genes during neurogenic phase, and unblocking expresses them during gliogenic phase).
Cerebellar Cortex Development – 4 Steps – (Outside In Development)
[Chizhikov Millen 2003]
Establish cerebellar field in hindbrain
Patterning of neural tube along dorsoventral and anterior-posterior axis
Anterior end of neural tube (forebrain), posterior end (midbrain, hindbrain, spinal
cord).
Cerebellum forms from anterior most rhombomere (7 rhombomeres) of hindbrain
Otx2, Gbx2 important in specifying midbrain-hindbrain boundaries (Otx2 expressed
anterior to boundary, Gbx2 expressed posterior – overlap forms boundary).
Chizhikov, Millen 2003 – Loss of Gbx2 causes expansion of midbrain region.
Chizhikov, Millen 2003 – IsoO also important in establishing anterior cerebellar
territory. Experiments to move IsO to anterior regions (in chick embryo) causes
ectopic midbrain and cerebellar development in graft areas.
Two compartments of cell proliferation
Thought to occur up until several days postnatally in mice.
Two regions involved in cerebellar development:
Rhombic lip – specialised region of ventricular zone (adjacent to IVth
ventricle roof) – gives rise to granule cell layer. Math 1 Gene – expressed in
rhombic lip (mutations causes complete loss of rhombic lip derivatives)
Cerebellar ventricular zone (adjacent to rhombic lip) produces precursors of
deep cerebellar nuclei and Purkinje Cells.
En1, En2 – important in ventricular zone, rhombic lip for correct cerebellar
folding
Migration of Cells – OUTSIDE IN
Migration of postmitotic cells from ventricular zone using radial glia LIKE
CEREBRAL CORTEX
Cells exit rhombic lip – migrate over surface and move inwards
Deep cerebellar nuclei leave rhombic lip first, descend ventrally – form 3 pairs of
nuclei
Granular cell precursors – form proliferative secondary precursor zone (EGL)
Granule cells leave EGL, migrate past PC to form IGL
Granule cell axons above PC form molecular layer
Migration guided by growth cones and molecular cues (e.g. netrins), stop cues.
Numb molecular cue needed for granule cell migration (Zhou 2011)
Reelin expressed by deep cerebellar nuclei and granular cells – GUIDES
PURKINJE CELLS (c.f. reelin expressed by Cajal-Retzius cells in cortex to guide
neurones)
Importance of reelin to arrange monolayer PC (otherwise form clumps).
Forming Cerebellar Circuity / Differentiation
Bergmann glia – differentiate into astrocytes (c.f. gliogenesis in cerebral cortex
development)
Massive increase in cerebellum size (gene expression, proliferation)
Purkinje Cells secrete Shh – control granule cell numbers
Stem Cells in Adults
Rats: Striatal subventricular zone (SVZ) lining lateral ventricles, Subgranular Zone
(SGZ) of hippocampus
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(SGZ) of hippocampus
SVZ cells are glial lineage (GFAP+ve) ‘Type B’ Cells, and unlike in embryonic
stage they are quiescent in adults. Can divide asymmetrically (maintain stem cell
pool).
Type B Cells can divide into Type C Cells that form Type A cells which are
neuroblasts, that can migrate to olfactory bulb (via rostral migratory stream) in rats –
which rely heavily on sense of smell.
Song et al (2012) showed how spill over GABA from surrounding neurons in SGZ
can stop stem cell proliferation (leaky synapses?). Leakage of GABA keeps stem
cells in quiescence.
Disorders of Cortical Development
Failure of proliferation – microcephaly
Failure of neuronal migration – periventricular heterotopia
Overmigration of neurons to pial surface – cobblestone lissencephaly
Reeler mouse mutants – gross malpositioning of neurons in cerebral and cerebellar cortex:
In cerebral cortex neurons fail to migrate past ‘older’ neuronal layers, and form
‘outside in’ development of cerebral cortex – wrong.
In cerebellum, reduced granule cell number and Purkinje Cells aggregate instead of
forming a monolayer.
Conclusion
Misc Notes:
Reelin binds to ApoER2 and VLDLR receptors on migrating neuroblasts, causing
downstream activation of Dab1.
Currently unsure whether Reelin acts as a ‘stop’ or ‘go’ signal, with evidence
suggesting and disproving both theories. Possible that Reelin may act as ‘go’ signal
during neuronal migration, and ‘stop’ signal once cells have reached correct cortical
level.
Studies have shown that increasing Dab1 degradation (i.e. reduced Reelin effects) causes
postmitotic neurones to fail to migrate past previous layer, while reduced Dab1 degradation
cause overmigration
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Document Summary
Compare and contrast the development of the laminar structure of the neocortex and cerebellar cortex, with a particular focus on molecular guidance and migration of cells. Embryonic development of the central nervous system is a highly complex and regulated procedure, which involves several inductive and inhibitory cues to ensure the development of the correct cells in the appropriate places. Variety of signalling pathways enables development/neurogenesis and proliferation of neurones that develop the cerebral cortex and cerebellum. Cortex - higher functions, cognition, initiating movement, processing sensory stimuli. Cerebellum works in sensing posture, balance and coordination, and generates patterns of muscle changes needed for movement. Also learns timing and sequence needed for new situations. Essentially judges errors between intended and actual voluntary movements adjusts motor pattern accordingly. Also now thought to have a role in cognition (e. g. linguistic, executive and visuospatial, as shown in cerebellar cognitive affective syndrome)=
