HTHSCI 1DT3 Study Guide - Quiz Guide: Facial Motor Nucleus, Interleukin 4, Prostaglandin E2

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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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The development, survival, maintenance and remodelling of neurons depends on the cytoskeleton.
Discuss.
Alzheimer’s Disease (Theory, biochemistry, APP, NGF) with relationship to transport failure?
Discuss the role of the neuronal cytoskeleton in intracellular transport, and how this is important in
neurogenesis and development.
Introduction
Cytoskeleton plays important role in mechanical strength, morphological plasticity/cell
movement and intracellular transport.
Acts as a cellular scaffold that gives cells (including neurones) structure. Found in all cells,
and plays a vital role in strengthening and transporting components through neuronal
axons and dendrites.
Cytoskeleton split into three protein components:
Microfilaments (smallest, actin, involved in morphological plasticity),
Intermediate filaments (variable, GFAP – astrocytes, neurofilament in neurones,
provide strength)
Microtubules (largest, organised physical cylinders, involved in cellular transport)
Particularly important during neurodevelopment neurones rely on cytoskeleton for
movement and pathfinding (immature neurons have growth cones that later develop into
presynaptic knobsrely on cytoskeleton to dynamically adjust growth cone movement).
Response to inductive and inhibitory cues allows for dynamic changes in cytoskeleton to
allow for precise control of neuronal development in CNS.
Actin filaments Morphological Plasticity
Actin filaments formed from actin subunits. Dynamic changes to actin filaments allow for
movement of growth cone during neurodevelopment, in response to particular cues that
can be attractive or repulsive.
Dynamic nature stems from Arp Complex and action of two key proteins: profilin and
cofilin. Profilin adds filaments to plus end and allows filament elongation, whilst cofilin is
involved with breaking down actin filaments tofree’ up available actin subunits to be used
at plus end (leading edge/growth cone).
Cofilin activity inactivated by phosphorylation (LIM Kinase), and reactivated by
dephosphorylation (slingshot).
Combination of profilin and cofilin allows plasticity changes in growth cone via actin
filaments, with support from microtubule that provides additional stability.
Actin cytoskeleton can also be influenced by Rho GTPases (from Ras molecular switch
family). RhoA stimulates stress fibres formation (involved in growth cone collapse), Rac1
stimulates Lamellipodia formation, Cdc42 stimulates fillopodia formation
(Rac1 + Cdc42 involved in growth cone advance and axonal growth).
Actin filaments also key in synapse function in synaptic plasticity (both during
development and adult?)involved in both presynapse (controls RESERVE POOL of
synaptic vesicles, and docking of READY-RELEASABLE POOL).
In postsynaptic membrane, actin meshworks hold protein and receptors in place and
control shape of spine.
Synaptic strength (and degree of plasticity?) associated with degree of actin polymerisation
in dendritic spines (postsynaptic membrane) influenced by Arp complex.
Intermediate filaments Axonal Strength
IF variable depending on cell type, with functions relevant to lineage.
GFAP in astrocytes, neurofilaments in neurones.
NF have high tensile strength, and providing good support especially given small diameter
and long lengths that axons can reach.
NF bend easily, difficult to break – providing support and enhancing survival of neurone.
Especially given the fact they need to last a lifetime (postmitotic).
Microtubules intracellular transport
Largest protein component of cytoskeleton, important in both developing neurons
(extending axons towards target tissues) and mature neurons (with established synaptic
connections).
Differences in MT between dendrites and axons.
MT stabilised by additional proteins (Tau in neurones, MAP2B in dendrites).
Axons MT arranged in uniform direction (same polarity) facing plus end
(towards growth cone/synapse), forming a transport track.
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Document Summary

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). o. 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) Patterning of neural tube along dorsoventral and anterior-posterior axis. Anterior end of neural tube (forebrain), posterior end (midbrain, hindbrain, spinal cord).