April 7, 2005

Molecular 'zipcode' guides nerves to correct places in body

Salk News

Molecular ‘zipcode’ guides nerves to correct places in body

La Jolla, CA – During embryonic development, thousands of nerves must be connected to muscles as part of a communication network that allows the newborn to move, breathe and lead a normal life. The question is, how does this complicated ‘telephone system’ get wired up?

In the April 8th edition of Cell, scientists at the Salk Institute for Biological Studies report that they have identified a molecular ‘zip code’ on the growing end of the nerve cell that guides it to the correct ‘address’ in the muscles. The discovery adds to developing knowledge about how the nervous system is assembled during fetal development. With such knowledge, researchers hope to use nature’s own tricks for repairing the nervous system damaged by injury or neurodegenerative disorders such as Lou Gehrig’s disease.

The complicated wiring process that occurs during embryonic development is controlled by chemical signaling molecules that guide the nerves to grow towards their targets. The Salk Institute study, involving a team of talented post-doctoral fellows led by Sam Pfaff and Tony Hunter, studied two key signaling molecules named ephrin and Eph.

Previous studies had established that the ephrin and Eph proteins work together as a tag team to guide the growth of neurons. Another Salk scientist, Dennis D.M. O’Leary previously revealed that Ephrins repel Ephs, so cells with the Eph ‘receptor’ on their outer surfaces will avoid cells producing the ephrin ‘signal.’

However, this apparently simple story is not quite so simple. Pfaff and other neuroscientists have long been puzzled by the fact that some neurons appear to produce both Eph and ephrin at the same time. Such an arrangement is baffling to scientists because it could lead to enormous confusion, since, in theory, the cell would end up ‘signaling’ itself – rather like calling your own telephone number and getting a busy signal.

Pfaff and colleagues showed that when Eph and ephrin are produced by the same cell, the two types of molecules are in different places on the cell membrane so they never have the chance to cancel each other out.

“The traditional view is that the Eph is the receptor in the neuron, and ephrin is the ‘message’ in the peripheral tissue,” said research associate Till Marquardt, a co-author on the paper. “We showed that not only can the same cell have both proteins, but they are found into different areas so they don’t short circuit one another.”

This arrangement – rather like having two separate phone lines going to phones in different rooms – allows the cell to receive two clear signals at the same time. The relative strength of the two signals gives the cell detailed information about its position. Thus, in effect, nerve cells are using the mosaic of ephrins and Ephs on their outer surfaces to create a detailed code.

This ‘zipcode’ allows them to fine-tune their navigation to the exact muscle the nerves are designed to communicate with.

“Prior to this study, we were thinking of the cell membrane of the neuron in a far too simplified way,” said Pfaff. “The nervous system is confronted with this challenge of having only a certain number of components that it can use and so it’s finding clever ways to create more complexity with a limited number of elements or starting points. Neurons can expand the diversity they get with just a couple of classes of proteins. This is a very satisfying solution.”

Insights such as these about how nerves grow into the right places in muscles could lead to new medical treatments for spinal cord injuries or neurodegenerative disorders, said Pfaff. “It certainly leads to some interesting questions about how you might rewire a functional motor network after spinal cord injury or replace diseased neurons with healthy ones in Lou Gehrig’s disease,” he said. “Moreover, these findings provide broad insight into how the brain is wired during fetal development.”

The Salk Institute for Biological Studies in La Jolla, California, is an independent nonprofit organization dedicated to making fundamental discoveries in the life sciences, the improvement of human health and the training of future generations of researchers. Jonas Salk, M.D., whose polio vaccine, which was proven safe and effective in 1955, has eradicated almost all cases of the crippling disease poliomyelitis, founded the Institute in 1960 with a gift of land from the City of San Diego and the financial support of the March of Dimes. Five years later, in 1965, the construction of the Institute was completed.

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