Sunday, November 11, 2012

How Nerve Meets Muscle and Begins to Talk

How Nerve Meets Muscle and Begins to Talk

By Sandra Blakeslee

FOR the first time, scientists report, they have been able to eavesdrop on a biochemical conversation that occurs during the wiring of nerves to muscles, deciphering a fundamental step in development. The findings may one day help scientists develop new treatments for nerve injuries and neuromuscular diseases like Myasthenia Gravis.

Scientists have long had a general idea of how nerves get wired up to muscles during development. The synapses, or chemical connections, between the two types of cells have been studied for well over 100 years. But the exact molecular steps involved in making the connection have remained a mystery.

Experiments described in the current issue of the journal Cell show that two substances -- one found on the tip of nerve cells, the other on the surface of muscle cells -- engage in a two-way conversation that plays a primary role in forming synapses.

The research is a breakthrough in understanding how nerve and brain cells interact, said Dr. Zach Hall, director of the National Institute of Neurological Disorders and Stroke. "It's not something that leads you to say, 'aha, now we know how a certain disease occurs,' " Dr. Hall said. "It's much more fundamental and in that sense important."

Dr. Joshua Sanes, of Washington University School of Medicine in St. Louis and colleagues developed strains of mice that lacked agrin, a molecule known to work in test tubes to cause muscle cells to develop receptors for an important neurotransmitter, acetylcholine, which travels across the synapse between nerve and muscle. That chemical is released by nerve cells.

Dr. Sanes and his colleagues wanted to go beyond the test tube, so they created mice that lacked agrin. The mice were stillborn. Their muscles did not function. Moreover, most of their synapses were malformed. Axons grew wildly over muscle and seemed unable to find their targets, suggesting that in life as well as in the test tube, agrin was essential for developing the connections between nerve and muscle.

Dr. George Yancopoulos, vice-president of discovery at Regeneron Pharmaceuticals Inc. in Tarrytown, N.Y., and colleagues pursued another part of the puzzle.

In searching for a chemical that would prevent muscle atrophy of the sort that might occur after nerve injuries, they found a substance they called MuSK, for muscle specific receptor kinase, that was situated right where nerve cell meets muscle cell: the neuromuscular junction.

They also developed a new strain of mice. Theirs lacked MuSK. The animals looked normal at birth but almost immediately they turned blue and died, Dr. Yancopoulos said. "We noticed their synapses were screwed up."

The two groups concluded that MuSK acted as a receptor for agrin, perhaps with other substances, and that the two chemicals together were necessary for the development of the neuromuscular junction. The Regeneron researchers suspect other factors may be involved and are continuing to study the development of the junction from the muscle side.

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