HTHSCI 1DT3 Quiz: Module 1 - Summaries.5
23 Jun 2018
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Found that tectum had an Ephrin A concentration gradient (high in posterior tectum,
low in anterior tectum). Temporal axons express high EphA receptors (so effects of
inhibition are greater) while nasal axons expressed fewer EphA (so were able to
grow further into tectum with higher Eprhin A concentrations).
Extracellular Matrix-Associated (e.g. Chondroitin Sulphate Proteoglycan)
Conclusion
As the above discussion illustrates, there are a number of different forms of guidance cues
that are present during neuronal development that are crucial to ensuring the precision with
which the correct neurones develop in the necessary locations.
Combination of positive and negative cues
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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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Document Summary
Found that tectum had an ephrin a concentration gradient (high in posterior tectum, low in anterior tectum). Temporal axons express high epha receptors (so effects of inhibition are greater) while nasal axons expressed fewer epha (so were able to grow further into tectum with higher eprhin a concentrations). o. As the above discussion illustrates, there are a number of different forms of guidance cues that are present during neuronal development that are crucial to ensuring the precision with which the correct neurones develop in the necessary locations. 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.
