Cerrebral navagation: How do nerve fibers know what direction to grow in?

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Cerebral navigation: How do nerve fibers know what direction to grow

in?

21 Apr 2005 Medical News Today

Nervous system development requires billions of neurons to migrate to

the appropriate locations in the brain and grow nerve fibers (axons)

that connect to other nerve cells in an intricate network. Growth

cones, structures in the tips of growing axons, are responsible for

steering axons in the right direction, guided by a complex set of

signals from cells they encounter along the way. Some signals lure

the axons to extend and grow in a particular direction; others are

inhibitory, making the axon turn away or stop growing.

In two papers in the April 21 Neuron, researchers from Children's

Hospital Boston reveal important insights into how inhibitory cues

affect the growth cone, and identify possible targets within axons

that could be blocked to overcome this inhibition. Such intervention

could possibly enable damaged axons to regenerate (normally

impossible in a mature nervous system) and ultimately restore nerve

function.

It's been known that cells synthesize an inhibitory protein called

ephrin, which binds to a receptor called Eph on the axon's growth

cone. But how this triggers the axon to change course or stop growing

has been a mystery.

" Very little has been known about the inner workings of the cell that

govern axon guidance, " says Greenberg, PhD, Director of the

Neurobiology Program at Children's and senior author on both

studies. " These studies begin to give insight into how the various

steps of axon guidance are controlled. "

The first paper found that when ephrin binds to Eph receptors on the

axon, it activates a protein called Vav2 in the cell's growth cone.

Activation of Vav2 induces the cell to engulf the ephrin-Eph complex,

breaking the bond between the two and repelling the axon, causing it

to turn away. When mice were genetically modified to lack Vav2 and

the related Vav3, thereby eliminating this repellent signal, the mice

had abnormal axon projections and defects in neural circuitry

formation.

The second paper demonstrates the role of a protein called ephexin1

in axon guidance. By itself, ephexin 1 promotes axon growth; neurons

from mice genetically modified to lack ephexin1 had significantly

shorter axons. But when ephrin is present and binds to Eph receptors,

ephexin1 is chemically modified, causing it to alter the cell's

cytoskeleton, or internal scaffolding. This alteration makes the

growth cone collapse, steering the axon in a new direction or halting

its growth. In chicken motor neurons whose ephexin1 was inactivated,

the axons grew into the hind limb prematurely, indicating faulty axon

guidance.

" Understanding these pathways could help in understanding the process

of nerve regeneration, " says Greenberg, who is also Professor of

Neurology and Neurobiology at Harvard Medical School. " The mechanisms

we've uncovered could provide opportunities for the development of

therapies for spinal cord injury, targeting ephexin and possibly

Vav, " he speculates, " but much more needs to be known about how

ephexin, Vav and other proteins work together to coordinate axon

guidance. "

For more information about the hospital visit:

http://www.childrenshospital.org/research.