HTHSCI 1DT3 Study Guide - Quiz Guide: Ultimate Tensile Strength, Lipid Bilayer, Blastocyst
23 Jun 2018
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actin filaments to ‘free’ 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).
Compartmentalisation
Importance of keeping axonal compartment separate from somatodendritic compartment.
Certain proteins, complexes etc need to be directed to particular regions of the neuron.
E.g. molecular machinery for exocytosis directed to synapse, growth factor receptors to
growth cone, NT receptors to dendritic spines.
Three mechanisms suggested:
Selective Delivery (delivery to specific relevant parts of cell)
Selective fusion (vesicles bud off golgi, travel in all directions. Only fuse in
relevant region).
Selective retention (vesicles fuse with all areas, but only kept in relevant region).
How is this barrier maintained?
Physical barriers – cell adhesion molecules (LI) form fence, prevents anything
passing through
Nakada (2003) suggested how a distinct diffusion barrier existed in the initial
segment of the axon and was one of the key ways in which neurones became
compartmentalisation. Associated with an accumulation and high concentration of
major cytoskeletal components (actin, ankyrinG).
Conclusion
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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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Document Summary
Actin filaments to free" up available actin subunits to be used at plus end (leading edge/growth cone). Importance of keeping axonal compartment separate from somatodendritic compartment. Certain proteins, complexes etc need to be directed to particular regions of the neuron. E. g. molecular machinery for exocytosis directed to synapse, growth factor receptors to growth cone, nt receptors to dendritic spines. Selective delivery (delivery to specific relevant parts of cell) Selective fusion (vesicles bud off golgi, travel in all directions. Selective retention (vesicles fuse with all areas, but only kept in relevant region). o. Physical barriers cell adhesion molecules (li) form fence, prevents anything passing through. Nakada (2003) suggested how a distinct diffusion barrier existed in the initial segment of the axon and was one of the key ways in which neurones became compartmentalisation. Associated with an accumulation and high concentration of major cytoskeletal components (actin, ankyring). o.
