L7: Axon growth and guidance

Question 1

What does axon growth, pathway finding and synapse formation depend on?

Answer 1

Extracellular guidance cues
Growth cone receptors
Cytoskeletal rearrangements
Changes in transcription in nucleus/local translation

CGCT: Cute goats cry tears.

Question 2

Discuss the outlines of development.

Answer 2

• Neurons extend axon towards appropriate tissue
• Molecular cues are required, as the path is long and circuitious. (Short or long, attractive or repulsive)
• The growth cone is enriched in receptors that detect cues and stimulate intracellular signalling pathways- cytoskeletal rearrangements.
• Cytoskeletal changes and growth cone dynamics control growth.
• Signals instruct growth cone to differentiate to presynaptic terminal
• Axon guidance often controls structural plasticity of synapses.

Question 3

Which 2 classes of molecules induce pre synaptic differentiation?

Answer 3

Wnt Family

Neurexin/Neuroligin

Question 4

What is activity dependent vs activity independent formation of the nervous system?

Answer 4

Formation of nervous system including outgrowth of axons, synaptogenesis etc is activity independent.

Activity dependent remodelling refines connections.

Question 5

What is the function of the Rho GTPases? Give 3 examples of GTPases.

Answer 5

These control microtubule dyanmics by causing actin assembly and dissassembly. Polymerase G actin -> F actin. Allows growth cone pathfinding.

Rho, Rac and Cdc42.

Question 6

Give examples of positive long range cues and their receptors. What receptor do all of these bind to?

Answer 6

Neurotrophins (NGF, BDNF, NT4/5, NT3)
NGF: TrkA
BDNF, NT4/5: TrkB
NT3: TrkC

Netrin: DCC

p75.

Question 7

What is the involvement of netrin with commissural neurons?

Answer 7

In the spinal cord, commisural neurons in the dorsal half are attracted ventrally by netrin 1 &2 gradients towards the floor plate. The neurons express DCC, allowing them to follow the gradient.

Question 8

Why is it beneficial that some neurons survive in the presence of certain receptors and others do not?

Answer 8

This allows for target selection- ensuring neurons do not innervate the wrong target cells. Misrouted neurons that have strayed to the wrong location will (and should) die.

Question 9

What are examples of positive short range cues?

Answer 9

Cell associated: NCAM (immunoglobulin), N-cadherin

ECM associated: Laminin (preferred by neurites) and collagen. (bind to B1 integrin RGD motif)

Question 10

NCAM neurite outgrowth is dependent on which 2 signalling pathways?

Answer 10

Fyn

Neuronal fibroblast growth factor receptor tyrosine kinase.

Question 11

How does laminin aid in visual development?

Answer 11

Guides retinal ganglion cells from retina to the optic tectum. This is laid by astrocytic end feet lining optic nerve path.

Question 12

Examples of negative long range cues?

Answer 12

Netrin: Unc5
Slit: Robo
Semaphorins: Plexins.

Question 13

Opposite to the commisural neurons, what does netrin do to trochlear motor neurons?

Answer 13

These neurons in the ventral half are repulsed by netrin, and grow dorsally AWAY from floor plate. This is due to Unc5 expression.

Question 14

Negative short range cues?

Answer 14

Cell associated: Ephrins- Type A . (GPI anchored) or Type B (transmembrane). Receptor Eph, activate Rho GTPases and growth cone collapse.

ECM associated: S-laminin, tenascin, CSPG