New clue to nerve growth may help regeneration efforts

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New clue to nerve growth may help regeneration efforts 16 Dec 2004

s Hopkins scientists have discovered how one family of proteins repels

growing nerves and keeps them properly on track during development. The finding,

described in the Dec. 16 issue of Neuron, might provide a chance to overcome the

proteins' later role in preventing regrowth of injured nerves, the researchers

say.

The proteins, known as chondroitin sulfate proteoglycans (CSPGs), have long been

known to prevent nerve regeneration after injury by recruiting a stew of other

proteins and agents, but exactly what part of the mix keeps nerves from

regrowing is unknown.

In studies of nerve growth in developing rats, the Hopkins scientists have

linked CSPGs' no-growth effects to a protein called semaphorin 5A. The

scientists, including Kantor, an M.D./Ph.D. candidate, found that when

CSPGs bind to semaphorin 5A, growing nerves are stopped in their tracks.

Blocking this particular interaction freed the nerves to continue growing.

" CSPGs are a critical obstacle to nerve regeneration after injury, and without

details about what's really happening, it's impossible to rationally intervene, "

says study leader Kolodkin, Ph.D., professor of neuroscience in s

Hopkins' Institute for Basic Biomedical Sciences. " We studied nerve growth,

rather than re-growth, but our work provides a starting point for identifying

more partners of CSPGs and for finding targets to try to counter these proteins'

effects in nerve regeneration. "

Semaphorins, including 5A, are a family of proteins that help direct growing

nerves as they extend toward their eventual targets, largely by keeping nerves

out of places they shouldn't be.

" These proteins are classic 'guidance cues' for nerves. There's nothing

particularly fancy about what they do -- they bind to spots on the tip of the

growing nerve, and the nerve doesn't continue going in that direction, " says

Kolodkin, whose lab studies semaphorins. " Scientists studying CSPGs' effects

haven't really been considering classic guidance cues as CSPGs' key partners,

but our study suggests they just might be. "

When a nerve is damaged, large amounts of CSPG proteins accumulate at the site

of injury. These proteins, in turn, draw in a host of other factors, including

semaphorins. Others have shown that without CSPGs, damaged nerves growing in a

dish can regenerate, a finding that suggests blocking CSPGs might permit the

same in animals.

In experiments in laboratory dishes, Kantor simulated a particular step in the

brain development of developing rats. During this step, specific nerves begin

connecting between what will eventually be two sections of the brain.

Because the accurate extension of these nerves requires semaphorin 5A, Kantor

was able to identify key molecules that interact with it. He found that CSPGs

bind semaphorin 5A to prevent nerves from extending across a no-man's-land

between the nerves' simulated origin and target. Preventing this interaction by

adding an enzyme that destroys only CSPGs allowed nerves to penetrate that space

when they shouldn't have.

Kantor also found that semaphorin 5A helps keep the bundle of growing nerve

fibers together by interacting with a different family of proteins, those known

as heparan sulfate proteoglygans (HSPGs). Other semaphorins also are known to

have the apparent paradox of both encouraging growth and restricting it.

" Semaphorins' dual abilities likely stem in part from interactions with

different partners, as we've seen here, " says Kolodkin, whose team is now

studying how semaphorin 5A's signal and binding partners change, and whether it

also partners with CSPGs to suppress regeneration. " During development, the

available partners change with time and place, helping a limited number of

guidance cues accomplish a very complex task. "

The Hopkins researchers were funded by the s Hopkins Medical Scientist

Training Program, the Reeve Paralysis Foundation, and the National

Institute of Neurological Disorders and Stroke.

Authors on the paper are Kantor, Kolodkin and Peer of s Hopkins;

Onanong Chivatakarn and Roman Giger of the University of Rochester, NY;

Oster and Sretavan, University of California, San Francisco; Masaru

Inatani and Yu Yamaguchi, The Burnham Institute, La Jolla, Calif.; and

Hansen and Flanagan, Harvard Medical School.