HTHSCI 1DT3 Study Guide - Quiz Guide: Neural Tube, Molecular Switch, Follistatin
23 Jun 2018
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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.
Protective Role – maintain BBB/repair BBB during damage to the CNS (proliferation of
astrocytes as part of reactive phenotype).
Upregulation of GFAP and chondroitin sulphate proteoglycan
Can become very fibrous
Form astrocytic scars (seals BBB) to form a continuous layer
BUT Astrocytes can stop axon regeneration by forming a molecular layer
which axons cannot pass to reconnect.
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Mechanisms of axonal growth and guidance (Short range soluble cues etc.)
Discuss the role of growth factors in CNS development
Introduction
The nervous system is an important but complex system of the body, and its development
requires precise control to ensure different regions of the body are appropriately innervated
by the correct neurones.
In order for this to occur, once initial nervous system development through key mitotic
divisions, the ability of neurones to extent axons towards their target tissue is largely
dependent on several molecular ‘cues’ to guide them to the correct location.
Molecular cues can be long or short acting, repulsive or attractive, and may have survival-
promoting properties.
Growth cone receptors on the terminal ‘growing’ end of the axon express specific receptors
(depending on the type of neuronal population, their location and role), and a degree of
receptor-specificity towards particular cues ensure that only the correct neurones with the
appropriate receptor will grow towards the ‘correct’ area.
Limiting target-derived trophic factor ensures that only the neurons that are ‘supposed’ to be
in a particular target tissue (expressing the correct receptors) are stimulated to survive.
Once axons have reached their target:
Key molecular cues help differentiate the growth cone into a synapse that can appropriately
attach with its target tissue.
Wnt – important secreted molecule stimulates pre-synaptic differentiation by
modulating microtubule dynamics in the growth cone.
Neurexin/Neuroligin – expression of neuroligin on the postsynaptic target cell binds
to neurexin receptors on the presynapse (growth cone), and stimulates presynaptic
differentiation into a fully formed synapse.
Idea that target and growth cone begins differentiating for their targets even before
reaching it.
Idea that synapses can form completely without any neuronal activity (i.e. purely
based on growth factors and axonal guidance cues).
However, after synapses have formed – need to have activity during critical period or
synapses are remodelled/lost (use it or lose it).
Synaptic plasticity – remodelling of synapses important for learning and memory.
Long Range Positive Cues
Netrin
Netrin 2 – Long Range, Gradual Gradient (highest in ventral region)
Netrin 1 – Short Range, Steep Gradient (higest in ventral region)
Netrin classically have been shown to act as long range positive cues in commissural
neurones that are found in the dorsal half of the spinal cord.
Respondent neurones express DCC Receptors (Deleted in Colorectal Cancer), which
binds Netrin and attracts them towards the ventral surface via changes in
concentration gradients.
Can act as long range chemorepulsive (negative) cues (e.g. trochlear neurones which
express Unc5 and DCC neurones) – example of how growth cues can be specific to
particular neuronal populations.
Neurotrophins – only receptors expressing the relevant neurotrophin receptor will bind and
be ‘rescued’, further evidencing how only the neurones that should be in a particular region
will grow e.g. NGF will only bind to growth cones expressing TrkA.
TrkA binds NGF (e.g. nociceptive neurons express TrkA) – Dimeric ligand causes
transautophosphorylation which stimulates intracellular cascades.
TrkB binds NT4/5, BDNF
TrkC binds NT3 (e.g. proprioceptive neurons express TrkC)
NGF discovered to have neurite promoting and survival effects.
NGF/TrkA – also implicated in Alzheimer’s disease:
NGF important to provide trophic support to enable cell survival
TrkA receptors transported by fast anterograde transport (cell membrane
associated component) – requires APP for fast anterograde transport.
Reduced functioning APP in AD (incorrect cleavage by beta/gamma
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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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