UC Berkeley/UC San Francisco researchers find protein with Jekyll-and-Hyde character -- it both blocks nerve growth and stimulates it

Released Jointly by UC Berkeley and UC San Francisco

Robert Sanders, Public Affairs

Two groups of neuroscientists tracking down what they thought were different proteins that guide the growth of nerve cells -- one an attractive protein, the other a repulsive one -- were startled to find they were homing in on the same one.

The discoveries, reported in three papers in the March 19 issue of Cell by researchers from the University of California, Berkeley, and UC San Francisco, show the amazing versatility of the nervous system. Depending on the situation, the nervous system is able to use the same protein for opposing functions.

The findings also provide insight into the process by which nerve cells grow and make their proper connections and may point to ways to stimulate regrowth after injury to the nervous system.

"This molecule, called 'Slit,' defines a new family of proteins that are likely to be one of the major classes of neural repellent proteins in animals and humans," said Corey Goodman, professor of molecular & cell biology at UC Berkeley, and an investigator in the Howard Hughes Medical Institute. "Yet, it also is the first known factor that, in a different context, causes nerve axons to branch -- a kind of positive regulator.

"Now that we know the bifunctional importance of this molecule in the nervous system, we can really begin to get an idea of how nerves grow and how we can jump-start growth after injury."

The head of the other group, Marc Tessier-Lavigne, a professor of anatomy and of biochemistry and biophysics at UC San Francisco who also is an investigator in the Hughes medical institute, compares the Slit protein to another molecule -- nerve growth factor, or NGF -- that causes nerve cells to branch. NGF, which operates mainly in peripheral nerves like those under the skin, is now in Phase 3 clinical trials as a way to stimulate regrowth of peripheral nerve cells damaged by diabetic neuropathy, a condition caused by diabetes.

"Slit can promote the extension and branching of the same axons that are the targets for NGF action," Tessier-Lavigne said. "It may therefore potentially be useful either alone or in conjunction with NGF for the same therapeutic indications."

The two groups work closely with one another, with Goodman and his lab colleagues concentrating primarily on the fruit fly Drosophila -- the most popular organism in which to study genetics -- and Tessier-Lavigne's lab working on mammals such as mice, rats and humans. Both are searching for the molecules that direct the growth of nerve cells in the developing organism.

A year ago the two reported finding a receptor that sits on the growing end of a nerve cell and sniffs out one of these control molecules. This receptor seemed to determine whether or not the nerve axon crossed the midline of the growing organism. The midline in a fruit fly larva is the equivalent of the growing spinal column in the embryo of a rat or human.

The gene coding for the receptor was dubbed roundabout -- Robo, for short -- because a mutation in the receptor in the fruit fly, where it was initially discovered, caused nerve axons to cross and recross the midline, creating loops like the European traffic circles called roundabouts. Normally such axons cross the midline only once, setting up the communication link between the left and right sides of the body.

At UC Berkeley, Goodman, postdoctoral fellow Thomas Kidd and graduate student Kimberly Bland now report that Slit is the molecule sniffed out by the Robo receptor. Goodman actually co-discovered the Slit protein with Spyros Artavanis-Tsakonas and his group at Yale University a decade

ago, but at the time had no proof it was involved in axon guidance. Now, they have shown that Slit is the repulsive signal detected by the Robo receptor.

In collaboration with Kidd, graduate student Katja Brose of Tessier-Lavigne's lab at UCSF was able to track down three similar genes in rats and humans, showing that the Slit gene is conserved in many animals as a regulator of nerve cell growth. They report this in a second article in Cell.

"It's essentially conserved from flies up to humans as a major repellent," Goodman said. "Slit defines a new and important family of repellents in the human central nervous system. To let nerve cells grow again, we will need to find ways to block its ability to inhibit growth."

The surprise came when Kuan-Hong Wang, another graduate student in Tessier-Lavigne's laboratory at UCSF, independently isolated a molecule that stimulates a different set of axons to branch. When the researchers looked at the protein closely, they saw that the molecule was identical to a piece of one of the mammalian Slit proteins.

"We had set out to study an entirely different biological phenomenon, the elongation and branching of sensory axons," Tessier-Lavigne said. "We developed a new approach, isolated, purified and identified the protein. When we found out it was Slit -- which our collaborators and we had just started to study for its repulsive effects -- we fell out of our chairs.

"Slit evidently has a Jekyll-and-Hyde character -- it can be repulsive or attractive depending on the type of neuron."

Wang, Tessier-Lavigne, Brose, Goodman, Kidd and two scientists -- David Arnott and William Henzel -- from Genentech Inc. of South San Francisco, report their findings on the branching activities of Slit in a third paper in the current issue of Cell.

An independent group of scientists based at Washington University in St. Louis also describe repulsive properties of the Slit protein in vertebrates in yet another paper in the current issue of Cell.

In developing embryos each nerve cell sprouts axons that snake through the embryo to connect with other nerve cells. At the tip of the axon is a growth cone that, like a nose, sniffs out signals along the way that tell the elongating axon to turn left, right or to continue on, until it finally connects with its target cell.

While an exciting advance in the field of nerve growth and regeneration, this most recent set of discoveries from the UC Berkeley and UCSF teams comes as no surprise to other scientists who have watched the pace of discovery and collaboration from these two labs over the past few years.

The two teams, both together and separately, have over the past decade been at the forefront of discoveries of many of the major proteins that control nerve growth and guidance, including the netrins and their receptors, and the semaphorins and their receptors.

Goodman and Tessier-Lavigne speculate that this Jekyll-and-Hyde character for Slit will be the norm and not the exception in the nervous system. They and other scientists have shown that other signaling molecules, such as the semaphorins and the netrins, are also bifunctional, affecting growing nerve fibers in different ways, depending upon the receptors expressed by the growing tip of the nerve fiber.

The combination of all these proteins and receptors allows a very rich array of interactions among nerve cells and exquisite control of how the nervous system gets wired. The hope for the future is that this knowledge of how the brain initially gets wired, that is, how nerve fibers grow and find their normal targets, will provide important insights into ways to make nerve fibers grow and sprout again and thus help repair injuries to the spinal cord and brain.

Goodman and Tessier-Lavigne speculate that the key likely will be finding the right cocktail of therapeutics that block the inhibitors and at the same time activate the stimulators.

Both groups are supported by the Howard Hughes Medical Institute, the National Institutes of Health and the American Paralysis Association.

(For a different version of this story and photos, go to HHMI's web site.)

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