HTHSCI 1DT3 Study Guide - Midterm Guide: Cdc42, Neuroglia, Neural Development
23 Jun 2018
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Reduced functioning APP in AD (incorrect cleavage by beta/gamma
secretase), leading to reduced trophic support and degeneration of ACh
neurones in Alzheimer’s.
Based on evidence that APP is necessary for axonal transport, vesicles for
APP contain TrkA,
Vossel (2010) – showed that presence of Tau and Aß reduced axonal
anterograde transport further.
Short Range Positive Cues
Cell-Cell Adhesion:
Immunoglobulin (NCAM, L1, TAG1) – neural cell adhesion molecule, is a cell-
associated transmembrane protein.
Several additional isoforms of NCAM are formed from alternate splicing:
PSA-NCAM – containing hydration sphere (stops NCAM from sticking to
each other), abundant in early development (promotes greater/faster neurite
outgrowth).
VASE-NCAM – scarce early in development, increases with development.
Poor substrate for neurite outgrowth – more adhesive than PSA (increases
interaction between cells).
NCAM can stimulate neurite outgrowth via FGF-receptors. FGF (fibroblast
growth factors) can stimulate neural cell survival and proliferation.
FnIII (Fibronectin Type-III domains) on NCAM proteins are suggested to
bind and activate FGFRs on neuronal cell surfaces and enhance neuronal
survival.
Cadherin – are able to bind stronger than NCAM
Extracellular Matrix
Laminin – guides axons during development by providing stimulatory signals for
growth. E.g. Retinal ganglion cells navigating from retina to the optic tectum via
laminin path laid down by astrocytic end feet.
When RGC reach target, they downregulate their integrin receptors.
Collagen
Major growth cone receptor for extracellular matrix is ß1-Integrins
Long Range Negative Cues
Netrin 2, Netrin 1
Trochlear motor neurones in ventral half of the spinal cord are repulsed by netrin,
and grow dorsally (away) from ventral surface. Repulsion is mediated by DCC and
Unc5 receptors (while DCC alone is chemoattractive).
Semaphorins
E.g. Semaphorin III are soluble chemorepulsants that stimulate growth cone collapse
Bind to plexin receptors
Slit
Soluble repellent secreted by midline cells that repulses neurons expressing Robo
receptors.
However, neurones that need to cross the midline do so under influence of
commissureless (Comm.) that causes downregulation of Robo Receptors, and
allows neurone to cross midline (under cues from netrin).
Once neurone has crossed the midline, Robo is re-expressed (as Comm is
downregulated), and stops neurone re-crossing back along the midline.
Short Range Negative Cues
Ephrin
Bind to Eph Receptors, and stimulate growth cone collapse (via tyrosine kinase
receptor activity that active Rho GTPase).
In vivo studies demonstrated Ephrin expression in optic tectum of tadpoles, where it
regulates growth of Retinal Ganglion Cells
(Temporal axons project to anterior tectum, while nasal axons project to posterior
tectum)
In vitro stripe assay showed temporal axons will not grow in posterior tectal
membranes, but nasal axons will grow equally on posterior and anterior tectal
membranes.
Found that tectum had an Ephrin A concentration gradient (high in posterior tectum,
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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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Document Summary
Reduced functioning app in ad (incorrect cleavage by beta/gamma secretase), leading to reduced trophic support and degeneration of ach neurones in alzheimer"s. Based on evidence that app is necessary for axonal transport, vesicles for. Vossel (2010) showed that presence of tau and a reduced axonal anterograde transport further. Immunoglobulin (ncam, l1, tag1) neural cell adhesion molecule, is a cell- associated transmembrane protein. Several additional isoforms of ncam are formed from alternate splicing: Psa-ncam containing hydration sphere (stops ncam from sticking to each other), abundant in early development (promotes greater/faster neurite outgrowth). Vase-ncam scarce early in development, increases with development. Poor substrate for neurite outgrowth more adhesive than psa (increases interaction between cells). Fgf (fibroblast growth factors) can stimulate neural cell survival and proliferation. Fniii (fibronectin type-iii domains) on ncam proteins are suggested to bind and activate fgfrs on neuronal cell surfaces and enhance neuronal survival. Cadherin are able to bind stronger than ncam o.
