Constant Cross-talk Between Motor And Sensory Nerves Keeps Growth Coordinated

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Constant Cross-talk Between Motor And Sensory Nerves Keeps Growth

Coordinated

http://medicalnewscenter.com/out/out.cgi?

http://www.sciencedaily.com/releases/2008/04/080410140516.htm

Come summer, we will once again marvel at the amazing athletic skills

of Olympic athletes while in fact, the simple act of walking is no

less remarkable. Just to prevent us from toppling over, the

neuromuscular circuitry that controls all bodily movements relies on

constant sensory feedback from the periphery to fine-tune its

commands to hundreds of muscles.

But it still remains unclear, how during embryonic development,

sensory and motor neurons become incorporated into tightly

coordinated pathways without getting mixed up. In a study, published

in the current issue of Science, scientists at the Salk Institute for

Biological Studies report that constant crosstalk between growing

sensory and motor neurons keeps them on track.

Skeletal muscle consists of thousands of muscle fibers, each

controlled by one motor neuron in the spinal cord that connects to

individual muscle fibers and relays signals from the brain. Sensory

stretch receptors, which are located in most muscles, as well as

temperature, pressure and pain receptors, all send information back

to the central nervous system.

" If you look at a cross section of a nerve bundle it really is a mix

of wires. Some wires are sending signals out from the spinal cord and

others are sending signals to the spinal cord, " explains

Pfaff, Ph.D, a professor in the Gene Expression Laboratory, who

together with former post doctoral fellow Till Marquardt, Ph.D., now

a group leader at the European Neuroscience Institute in Göttingen,

directed the study. " The motor and sensory nerves are not unlike a

roadway with orderly traffic moving in both directions by staying in

its proper lanes, " he adds.

During embryonic development, nerve cells hesitantly extend tentacle-

like protrusions called axons. Growth cones, small enlargements at

the axons tip actively search their local environment for chemical

cues that guide them to their target. One such cue comes from a class

of molecules called ephrins, which repel cells carrying Eph proteins,

gently nudging them in the right direction.

The traditional view was that growth cones studded with Eph proteins,

which take on the role of receptors, search their environments for

ephrins, which take on the role of ligands. During his time as a

postdoctoral researcher in Pfaff's laboratory, Marquardt discovered

that neurons not only carry both types of proteins, but that the role

of ephrins and Ephs can change as well.

" The fact that neurons can express receptors and ligands and that

everything can be a receptor or ligand, raised the question what

happens when you have two neurons that grow beside each other and

occasionally bump into one another, " says Pfaff. To answer the

question, the Salk researchers settled on sensory and motor neurons,

which extend their axons along the same pathway to the periphery.

First, co-first authors W. Gallarda, and Dario Bonanomi,

Ph.D., generated mice that allowed them to genetically distinguish

between sensory and motor neurons with different " labels " . With

ephrin/Eph signaling intact, their axons joined up after they emerged

from the spinal cord but sorted into separate fascicles containing

either sensory or motor axons, but never both. When the researchers

deleted EphA3 and EphA4 in motor neurons, interrupting the cross talk

across the highway divide, things started to go severely wrong.

The sorting between the fascicles of the motor and sensory axons

broke down and instead of reaching for muscles, some motor neurons

left their lane, made a U-turn, joined the sensory lane and headed

back toward the spinal cord. " It was a real wiring disaster, " says

Pfaff. " It appears that ephrin and Eph not only control the decision

where these axons grow out in the periphery but also maintain the

normal arrangement between the motor and sensory pathway. "

The ephrin/Eph tag team not only helps the body's motor nerve cells

grow along their proper paths during embryonic development, it also

plays a major role in preventing spinal cord neurons from

regenerating after injuries. Hoping to coax injured neurons into

rewiring severed connections, researchers in the spinal cord field

are hard at work trying to overcome the block that prevents axonal

growth within the central nervous system.

" Our findings emphasize that this needs to be done cautiously. If you

promote indiscriminate motor axon growth it could cause a lot of

problems, " cautions Pfaff. " There are many examples of extensive

neuronal reorganization following spinal cord injuries and one often

underappreciated byproduct is severe pain. "

Researchers who also contributed to the study include Müller,

Ph.D., a post-doctoral researcher in the Marquardt laboratory, Arthur

Brown, Ph.D., associate professor at the University of Western

Ontario, Canada, postdoctoral researchers A. Alaynick, Ph.D.,

Shane E. s, Ph.D., both in the Pfaff laboratory, and Greg

Lemke, professor in the Molecular Neurobiology Laboratory at the Salk.