Axon Guidance 2

Question 1

What is the role of Immunoglobulin (Ig) superfamily of cell adhesion molecules (CAMs)?

Answer 1

Mostly support axon growth

(MAG inhibits the growth of post-natal axons)

MAG is a myelin associated inhibitor of axonal growth

Question 2

What are the characteristics of the Immunoglobulin (Ig) superfamily of cell adhesion molecules (CAMs)

Answer 2

Characterised by Ig domains though most have fibronectin type 3 repeats

Question 3

What are the 3 main types of Immunoglobulin (Ig) superfamily of cell adhesion molecules (CAMs)?

Answer 3

• Classical CAMs include NCAM and L1
• Receptor protein tyrosine phosphatases – characterised by intracellular phosphatase domains activated on ligand binding
• Receptor tyrosine kinases – characterised by intracellular kinase domains activated by ligand binding

Question 4

What electrolyte are cadherins dependant on?

Answer 4

Ca2+-dependent cell adhesion molecules

Question 5

What is the main cadherin expressed in the nervous system?

Answer 5

N-Cadherin

Question 6

What is the role of N-Cadherin?

Answer 6

Supports axon growth

Probably involved in axon piggy backing along other axons

Question 7

What extracellular matrix molecules are involved in support of growth?

Answer 7

Laminin and fobronectin

Question 8

What extracellular matrix molecules are involved in inhibition of growth?

Answer 8

Tenascin usually and chondroitin sulphate proteoglycans

Question 9

What are the receptors for extracellular matrix proteins?

Answer 9

Mostly integrin receptors

No Known receptors for proteoglycans

Question 10

Where can you find extracellular matrix proteins?

Answer 10

Most concentrated in basal laminae, though also expressed and secreted by glial cells such as Schwann cells and astrocytes

Question 11

What is the activity of Netrins?

Answer 11

can both attract or repel axons, depending on class of axon and/or stage of development

Question 12

What are the three types of netrin receptors?

Answer 12

3 types of receptors: DCC (for attraction), unc5 (for repulsion) and adenosine A2bR (possibly involved in netrin-induced regulation of intracellular cAMP – controversial)

Question 13

What are slits?

Answer 13

Secreted ECM molecules

Question 14

What do slits bind to?

Answer 14

Slits bind to robo receptors

Question 15

What is the action of slits?

Answer 15

Mostly cause axon repulsion

Can silence Netrin signalling through DCC

Question 16

What is the action of semaphorins?

Answer 16

Mostly associated with axon repulsion

Mostly seem to signal with RhoA GTPase causing growth cone collapse

Question 17

What are the receptors for semaphorins?

Answer 17

Plexin receptors A and B

Class 3 semaphorins also require europilin co-receptors and in some cases L1

Question 18

What are the two groups of ephrins?

Answer 18

A (GPI-anchored) and B (transmembrane)

Question 19

What are the two groups of ephrin receptors?

Answer 19

A and B

Question 20

What is the action of ephrins?

Answer 20

Ephrins largely thought to cause axon repulsion, though in the tectum Ephrin Bs may function by attraction

Ephrin Bs can signal both as ligands and receptors: 2-way signalling

Expressed in gradients in tectum as well as at midline structures such as the optic chiasm

Tectum = the uppermost part of the midbrain, lying to the rear of the cerebral aqueduct.

Question 21

What are the 3 main types of myelin protein?

Answer 21

3 main types: Nogo, myelin associated glycoprotein (MAG) and oligodendrocyte myelin glycoprotein (OMgp)

Question 22

What is the receptor for the myelin proteins?

Answer 22

All signal through the Nogo receptor, which requires p75 co-receptor

Question 23

Myelin proteins -

Thought to be major reason why mammalian CNS axons do not regenerate

Knock-outs have produced varied results, with some reports of enhancing regeneration and some with no effect

Question 24

What is the role of sema-2-a in the developing limb of a grasshopper

Answer 24

Sema-2a appears to drive neurite initiation towards the CNS by repulsion from distal limb areas, where Sema-2a is most strongly expressed

Question 25

What axon guidance proteins are involved in the commisural axons in the neural tube?

Answer 25

Bone morphogenetic proteins, semaphorins and ephrins are thought to repel the growing axons from the roofplate

Netrin attracts the axons to the floor plate as they grow across the basement membrane to the ventral half of the neural tube

The combination of attraction to slits expressed in the midline and loss of sensitivity to netrin results in anterior growth towards the brain and no growth back across the floorplate

Question 26

Describe the regeneration of axons in the CNS after injury

Answer 26

Unlike the PNS, the CNS in postnatal animals becomes inhibitory to the regeneration of axons after injury.

Question 27

Why might the regeneration of axons in the CNS in postnatal mammals be poor?

Answer 27

One clear possibility is that inhibitory molecules are upregulated in the nerve environment, perhaps concomitant with a decline in supportive molecules. This is especially true of CNS myelin.

However, embryonic neurons transplanted into adult brains can grow axons, and in vitro embryonic neurons can grow processes even on myelinated nerves, while their older counterparts cannot. This would suggest that intrinsic developmental changes in neurons are at least as important as environmental considerations in rendering neurons incapable of regenerating axons.

So inhibitory molecules, decline in supportive molecules and intrinsic changes in the neurons.

Question 28

What are the cells that make CNS myelin?

Answer 28

Oligodendrocytes

Question 29

How does cAMP activity change in development?

Answer 29

Known to decline (declines as RGC axons start to become repelled by certain molecules they used to be attracted to)

(Also declines when MAG starts to be recognised as an inhibitor by sensory neurones)

Question 30

How do levels of cAMP mediate both chemoattraction and chemorepulsion?

Answer 30

Epac (exchange protein activated by cAMP) is more active when cAMP levels are relatively high - mediates chemoattraction and and enhances the rate of sensory axon growth.

When cAMP levels decrease the activity of epac also decreases and protein kinase A signalling takes over (PKA). PKA mediates chemorepulsion and does not promote sensory axon growth.

Thus a decline in endogenous cAMP levels could play a role in the transition between a CNS that supports axon growth and one where axon regeneration does not occur.

Question 31

RGC axons only become sensitive to semaphorin in later development, when they upregulate semaphorin receptors. It seems likely then that such intrinsic changes to the complement of receptors expressed by growth cones, and the signalling molecules expressed within, underlie the onset of axon growth inhibition in the CNS. Much is yet to be resolved.