What is the role of Immunoglobulin (Ig) superfamily of cell adhesion molecules (CAMs)?
Mostly support axon growth
(MAG inhibits the growth of post-natal axons)
MAG is a myelin associated inhibitor of axonal growth
What are the characteristics of the Immunoglobulin (Ig) superfamily of cell adhesion molecules (CAMs)
Characterised by Ig domains though most have fibronectin type 3 repeats
What are the 3 main types of Immunoglobulin (Ig) superfamily of cell adhesion molecules (CAMs)?
- 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
What electrolyte are cadherins dependant on?
Ca2+-dependent cell adhesion molecules
What is the main cadherin expressed in the nervous system?
What is the role of N-Cadherin?
Supports axon growth
Probably involved in axon piggy backing along other axons
What extracellular matrix molecules are involved in support of growth?
Laminin and fobronectin
What extracellular matrix molecules are involved in inhibition of growth?
Tenascin usually and chondroitin sulphate proteoglycans
What are the receptors for extracellular matrix proteins?
Mostly integrin receptors
No Known receptors for proteoglycans
Where can you find extracellular matrix proteins?
Most concentrated in basal laminae, though also expressed and secreted by glial cells such as Schwann cells and astrocytes
What is the activity of Netrins?
can both attract or repel axons, depending on class of axon and/or stage of development
What are the three types of netrin receptors?
3 types of receptors: DCC (for attraction), unc5 (for repulsion) and adenosine A2bR (possibly involved in netrin-induced regulation of intracellular cAMP – controversial)
What are slits?
Secreted ECM molecules
What do slits bind to?
Slits bind to robo receptors
What is the action of slits?
Mostly cause axon repulsion
Can silence Netrin signalling through DCC
What is the action of semaphorins?
Mostly associated with axon repulsion
Mostly seem to signal with RhoA GTPase causing growth cone collapse
What are the receptors for semaphorins?
Plexin receptors A and B
Class 3 semaphorins also require europilin co-receptors and in some cases L1
What are the two groups of ephrins?
A (GPI-anchored) and B (transmembrane)
What are the two groups of ephrin receptors?
A and B
What is the action of ephrins?
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.
What are the 3 main types of myelin protein?
3 main types: Nogo, myelin associated glycoprotein (MAG) and oligodendrocyte myelin glycoprotein (OMgp)
What is the receptor for the myelin proteins?
All signal through the Nogo receptor, which requires p75 co-receptor
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
What is the role of sema-2-a in the developing limb of a grasshopper
Sema-2a appears to drive neurite initiation towards the CNS by repulsion from distal limb areas, where Sema-2a is most strongly expressed
What axon guidance proteins are involved in the commisural axons in the neural tube?
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
Describe the regeneration of axons in the CNS after injury
Unlike the PNS, the CNS in postnatal animals becomes inhibitory to the regeneration of axons after injury.
Why might the regeneration of axons in the CNS in postnatal mammals be poor?
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.
What are the cells that make CNS myelin?
How does cAMP activity change in development?
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)
How do levels of cAMP mediate both chemoattraction and chemorepulsion?
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.