Developing nervous system sculpted by opposing chemical messengers

in medical conditions such as spinal cord injury.

Lee, along with Salk colleagues Weichun Lin, Bertha Dominguez, Jiefei Yang, Prafulla Aryal, Eugene Brandon and Fred Gage, discovered that the creation of synapses is controlled by the nerves themselves. As they grow towards the muscle cells, the nerve cells release a powerful chemical messenger from their growing ends. Called acetylcholine, this neurotransmitter 'edits out' the potential synapse sites on the muscle cell not destined to connect to a nerve. In mature animals, acetylcholine is a key neurotransmitter responsible for transmitting signals between nerve cells and muscle.

Using a combination of genetic and pharmacological techniques to block the various components of the chemical pathways involved, the Salk researchers painstakingly showed that acetylcholine works in tandem with another chemical produced by nerve cells, called agrin. Where the end of the nerve touches the muscle cell, agrin is concentrated enough to overcome the 'editing' effect of the acetylcholine. Further away from the nerve end, the levels of agrin are not high enough to overcome the more powerful influence of acetylcholine, and the redundant synapse sites are dismantled.

"The result is an interesting mechanism whereby two opposing forces work together to create the crucial synaptic connections between motor neurons and muscle cells," said co-author Prafulla Aryal.

"Although we have suspected for 25 years that something like this was happening, until now no-one has been able to demonstrate it in a living system," said Lee. "It is likely that this process occurs all over the nervous system. If you're going to repair or regenerate nerves in, for example, spinal cord injury you need to know how to form synapses for the right connections to be made."


Contact: Cathy Yarbrough
Salk Institute

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