Nerves' Growth Depends on Dual-Action Protein

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Nerves' Growth Depends on " Dual-Action " Protein

By: s Hopkins Medicine on Jul 23 2005 09:39:39

Nerve Damage

Finding is important step toward efforts to regrow damaged nerves

By studying nerves in " pre-tadpole " frogs, researchers at the s

Hopkins Institute for Cell Engineering have uncovered the first link

between two key biological factors that guide growing nerves.

The finding sheds light on how nerves grow in the right direction so

they can connect to the right places, critical information to have if

damaged nerves are ever to be repaired in people. In particular, the

discovery reveals for the first time how the guidance cues that

attract or repel the tip of a growing nerve influence the flow of

calcium ions into the nerve cell, solving a decades-old mystery.

" For 20 years researchers have known that calcium flow is critical

for proper nerve growth, but no one has known how it gets into the

nerve in response to a guidance cue, " says Guo-Li Ming, M.D., Ph.D.,

assistant professor of neurology in the Institute for Cell

Engineering's Neuroregeneration and Repair Program. " Now we have some

details about how that happens in frogs. The findings are likely to

hold for other animals and people, too, because we have similar

versions of these proteins. "

In the June issue of Nature Neuroscience, the Hopkins team shows that

a " dual-action " protein connects guidance cues and the calcium flows

that allow the nerve to respond to those cues. This protein, called

TRPC1 or transient receptor potential channel 1, lets calcium into

the nerve's growing tip once it is " turned on " by certain guidance

cues. Furthermore, in pre-tadpole-stage frogs, TRPC1 is required for

a specific set of nerves in the spinal cord to grow properly.

The s Hopkins scientists' research confirms a recent report that

laboratory-grown frog nerves rely on TRPC1 activity to help direct

the nerves' axons, and it shows for the first time that the protein

is required for normal nerve growth in the actual frog.

" Frogs have only TRPC1, but humans have a whole family of TRPC

proteins, including several analogous to the frog's TRPC1, " says

Ming. " It's likely that the same role is being played by these

proteins during human development. "

But TRPC1 also may play a role later in life, when guidance cues in

the brain and spinal cord tell nerves not to regrow if they are

damaged. Understanding exactly how these cues influence nerve cells

could help efforts to overcome their signals and get damaged nerves

to regrow their axons and reform lost connections.

" We also found that TRPC1 triggers calcium influx in response to

myelin-associate glycoprotein, a molecule that helps prevent the

regrowth of damaged nerves in adults, " says Ming. " If this is also

true in people, it could be critical to trying to get around myelin's

growth-inhibiting effects. "

The researchers' experiments also show that TRPC1 is used for

detecting and reacting to attractive guidance cues netrin-1 and brain-

derived neurotrophic factor during development. There are likely to

be many others, the scientists say.

TRP channels were first identified by Craig Montell, professor of

biological chemistry and neuroscience at s Hopkins, and were

already known to help cells sense heat and pain.

" Now we've shown that they also are likely to be critical for proper

nerve growth during embryonic development and to be part of the

machinery that prevents nerve regrowth later in adulthood, " says

study co-author Hongjun Song, Ph.D., also an assistant professor of

neurology in ICE's Neural program.

Situated in the spinal cord of the frog, the nerves affected by TRPC1

use it at least in part to extend their tentacle-like axons along the

circumference of the spinal cord toward and then across the cord's

midline. Each axon then branches and shoots one branch along the

length of the spinal cord toward the brain and the other " down "

toward the animal's legs.

To study TRPC1's effects in frogs, the researchers used a number of

different methods to interfere with the ability of one side of the

animal's spinal cord to react to the protein. In one set of

experiments, the researchers injected the equivalent of interfering

RNA (DNA's cousin) into one cell when the developing frog was at just

a two-cell stage. Because each of the cells develops into half the

frog, one side is normal, and one side can't make sufficient amounts

of TRPC1.

The researchers discovered that interfering with TRPC1 prevented many

of the growing nerves from reaching or crossing the midline of the

spinal cord in the developing frogs.

" This is a major breakthrough in understanding how calcium gets into

these cells in response to guidance cues during development, " says

Song.

Authors on the paper are Sangwoo Shim, Eyleen Goh, Shaoyu Ge, Kurt

Sailor, ph Yuan, Worley, Song and Ming, all of s

Hopkins; and Llewelyn Roderick and Bootman of the Babraham

Institute, Cambridge. The Hopkins researchers were funded by the

National Institute of Neurological Disorders and Stroke, E.

Culpeper Scholarships in Medical Science, the Whitehall Foundation,

and the Basil O'Connor Starter Scholar Research Award Program to Guo-

li Ming. Sangwoo Shim is partially supported by a postdoctoral

fellowship from the Korea Science and Engineering Foundation.

-JHMI-