Axon Guidance 2 Flashcards
(49 cards)
What is the Ig superfamily and give the 3 main types
Homophilic (bind to same Ig on axon and cell surface for cell adhesion and axon growth. The three main types -
- 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 are the cadherin subfamilies
Calcium dependent cell adhesion molecules that link cadherins to cytoskeleton (anchor-like)
The axon can grip to substrate and pull itself along. Bind homophillically
Give some examples of extracellular matrix molecules and how they bind to axons to help with axon guidance
Through integrin receptors. Secreted by schwann cells and astrocytes
Examples include - laminin (very effective) and fibronectin (supportive)
Tenascin and proteoglycans (inhibitory usually)
What are netrins
4 receptor types which attract or repel axons depending on class of axon and/or stage of development.
Forms gradients.
- DCC
(attraction), UNC5 (repulsion) and adenosine A2bR (cAMP induced attraction)
What substance is important for promotion of axon guidance in netrins
Netrin binds to DCC dimers and activates
- cAMP
- cAMP then activates Rho GTPase, cdc42 and Rac1
What happens if UNC5 binds in axon guidance
Repulsion - but causes unknown.
What happens if A2bR is blocked (type of netrin)
Prevents netrin induced growth cone guidance as its role is to activate adenylate cyclase via g protein which promotes cAMP
What are slits
Motifs (short recurring patterns of DNA) that is expressed by ECM molecules. They are inhibitory for axon growth but are important for branching.
They are the ligand for robos
What are Robos
Slit receptors (part of Ig superfamily)
What happens when slits bind to robo
May silence the function of netrin-DCC
AND/OR
Inactivate cdc42 through GAP regulation
What are semaphorins role in axon guidance
large family, mostly associated with axon repulsion
What are the families of semaphorins
2 families of plexin receptors (A and B)
How do semaphorins signal
Binding to integrins and plexins - through RhoA GTPase, causing growth cone collapse -
What are ephrins and how do the manipulate growth cone guidance
2 groups: A (GPI-anchored) and B (transmembrane).
Ephrins largely thought to cause axon repulsion, though in the dorsal side of midbrain Ephrin Bs may function by attraction
How are ephrins expressed
As ligands or recetpors - 2-way signalling.
Expressed in gradients in midline structures (optic chaism) and midbrain
What are the 3 main types of myelin proteins in axon guidance
Nogo
myelin associated glycoprotein (MAG)
oligodendrocyte myelin glycoprotein (OMgp)
How do the 3 types of myelin proteins signal
All signal through the Nogo receptor, which requires p75 co-receptor which then activates RhoA and inhibits growth cone events
Why are myelin proteins important
Thought to be major reason why mammalian CNS axons do not regenerate as inhibitory for axon guidance in the CNS
Has varied knockout results
Give an example in developing grasshopper limbs of how guidance signals combine their effects
Legg and O-connor 2003
Sema-2a REPLSION = drives neurite initiation towards the CNS by repulsion from distal limb areas, where Sema-2a is most strongly expressed.
When sema-1a removed - poor path finding within trochanter boundary but still manages to travel in general direction to make contact with Cx1 cells
Give an example in developing embryos of how guidance signals combine their effects
Commissural axons in the neural tube are thought to be repelled from the roofplate by a number of repulsive molecules -
bone morphogenic proteins (BMPs),
Semas
Ephrins
They then appear to grow along the basement membrane into the ventral half of the neural tube, where they are attracted to the floorplate by netrin. Keeping the CNS central
What happens when these axons cross the floorplate in embryo development
axons acquire sensitivity to slits expressed in the midline due to an increase in robo, and may also lose sensitivity to netrin by silencing DCC.
Thus, they do not grow back across the floorplate, but turn and grow anteriorly towards the brain and therefore keeping the CNS within the midline
What is one major difference between the PNS and CNS regarding axon growth
Unlike the PNS, the CNS in postnatal animals becomes inhibitory to the regeneration of axons after injury.
The PNS contains schwann cells which are supportive of axon growth.
Why is the CNS inhibitory postnatally to regeneration
One clear possibility is that inhibitory molecules are upregulated in the nerve environment, perhaps concomitant with a decline in supportive molecules.
Explain how the CNS differs from the PNS during their responses for cell injury.
Oligodendrocytes - CNS cells that produce myelin - are upregulated to inhibit the CNS production. Degeneration doesn’t occur.
Microglia produce inhibitory substances.
Inhibits axon growth.
In the PNS, wallerian degeneration occurs where the myelin degenerates and the schwann cell moves into the basal lamina tube and macrophages arrive. Schwann cells divide and they remove the cytoskeleton debris with the macrophages and the schwann cells form new axons.
Wallerian degeneration is CRUCIAL for regeneration. this doesn’t happen in the CNS.
