HTHSCI 1DT3 Study Guide - Quiz Guide: Notochord, Vldl Receptor, Neural Groove
23 Jun 2018
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Describe neuronal polarity and compartmentalisation, and discuss its importance for neuronal
function
Introduction
Neurones are a fundamental component of the central nervous system, and are highly
specialised in their role of initiating, conducting and modulating signals in the complex
circuitry of the brain.
There can be many different neurone subtypes (unipolar, bipolar, multipolar), but for the
purpose of the essay we will consider multipolar neurones (found most abundantly in the
CNS), which have multiple dendrites and a single axon.
Neurone can be split into the soma, dendrite, axon and synaptic regions.
Dendrites receive input from other neurones in the CNS by synaptic transmission (dendritic
spines), which can either be excitatory (increase likelihood of firing, e.g. glutamate, ACh)
or inhibitory (decreased likelihood of firing e.g. GABA). Sum of excitatory and inhibitory
signalling helps modulate and determine the likelihood of that particular neurone firing.
Neuronal polarity refers to the development of distinct morphological areas of cells that are
differentiated to perform varying functions – same is true for the dendritic and axonal
compartments of the neurone, that have specialised molecular and cytoskeletal layouts.
Key differences in compartment
Axon-Specific:
Presence of neurofilaments only in axons (strength role)
Aligned microtubules (all face soma) – important for retrograde and anterograde
transport
Microtubule stabilising protein – Phosphorylated Tau
Cell adhesion molecules – L1 (NgCAM), TAG-1
Presence of neurotransmitters, growth factor receptors, SNARE complexes which
are required at the presynapse
Dendrite-Specific:
Microtubules are of mixed polarity (i.e. not aligned)
Microtubule stabilising protein – MAP2B
Neurotransmitter receptors, post-synaptic density scaffolding, signalling proteins
required at postsynapse
Development of axon
Before compartmentalisation occurs neuronal progenitors must form an axon.
Polarisation of the neuronal progenitors to form the axon is determined by a combination
of cell intrinsic factors and extracellular guidance and a balance of positive and negative
growth cues.
Initially neurones extend several short neurites – one starts growing faster than the others
(through a greater positive cue effect) and forms the axon.
Other neurites default to forming dendrites (once axon is specified, a powerful negative cue
is sent to other neurites so only one axon is generated).
Importance of growth factors in growth of axon:
Positive Long Range Cues (Netrins – DCC, Neurotrophins – TrkA,B,C)
Positive Short Range Cues (NCAM – FnIII activation of FGF, Cadherin)
Negative Long Range Cues (Slit – ROBO, Comm., Semaphorins - Plexins, Netrins –
Unc5 and DCC in Trochlear MN)
Negative Short Range Cues (Ephrins – Nasal RGC axons can extend to posterior
tectum as they have low EphA Receptors, Temporal axons can only extend to
anterior tectum as they have high EphA Receptors, greater EphA in posterior
tectum, Chondroitin Sulphate Proteoglycan)
Role of Wnt/Neurexin-Neuroligin Binding in forming the synapse from the growth cone
Once axon is specified, dynamic growth occurs and the growth cone (at end of axon) is
sensitive to external guidance cues that allows it to grow correctly towards its destination –
mainly mediated through changes to microfilaments (actin).
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.
Arp Complex and action of two key proteins: profilin and cofilin. Profilin adds
filaments to plus end and allows filament elongation, whilst cofilin breaks down
actin filaments to ‘free’ up available actin subunits to be used at plus end (leading
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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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Document Summary
Describe neuronal polarity and compartmentalisation, and discuss its importance for neuronal function. Neurones are a fundamental component of the central nervous system, and are highly specialised in their role of initiating, conducting and modulating signals in the complex circuitry of the brain. There can be many different neurone subtypes (unipolar, bipolar, multipolar), but for the purpose of the essay we will consider multipolar neurones (found most abundantly in the. Cns), which have multiple dendrites and a single axon. Neurone can be split into the soma, dendrite, axon and synaptic regions. Dendrites receive input from other neurones in the cns by synaptic transmission (dendritic spines), which can either be excitatory (increase likelihood of firing, e. g. glutamate, ach) or inhibitory (decreased likelihood of firing e. g. gaba). Sum of excitatory and inhibitory signalling helps modulate and determine the likelihood of that particular neurone firing.
