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Getting nervous
By Bijal P. Trivedi

How a single nerve cell navigates through the spaghetti-like tangle of neurons in the brain to make a specific connection with another neuron is still pretty much a mystery. But scientists at the University of California, Los Angeles, and the University of Michigan have found an intriguing molecule that may be part of the answer.

Dscam receptors at the tip of the neuron receive signals from different parts of the brain, controlling the direction of growth.

A receptor called Dscam, which is embedded in the outer membrane of the neuron, receives signals sent by other cells and these messages affect the direction in which the neuron grows. Some signals repel, and others attract.

Dscam, which was found in the fruit fly Drosophila melanogaster, is the fly version of the human Down Syndrome Cell Adhesion Molecule (DSCAM), which is thought to be associated with mental retardation.

The researchers found that when the Dscam receptor malfunctions, the long stringy growth cone cannot find its target. To study the effects of Dscam mutations, the researchers focused on Bolwig's organ, the embryonic predecessor of the fly's eye, which contains a bundle of 12 neurons that first grow toward a target neuron—P2—before traveling to the brain. In many Dscam mutants the neurons were unable to find the P2 neuron. Whether neurons lose their targeting ability in Down syndrome patients is not known.

What researchers find most interesting about Dscam is that it is a modular gene with 24 segments, or exons. There are many versions of exons 4, 6, 9, and 16, all slightly different, any one of which can be used to make a Dscam; exon 4 has 12 alternatives, exon 6 has 48, exon 9 has 33 and exon 17 has 2.

With the alternative forms of exons 4, 6, 9, and 17, there are 38,016 possible variations of the Dscam gene. Whether all these forms are actually produced by the cell is not known, says Jack Dixon, who led the biochemical experiments in the study at the University of Michigan.

The different versions of the Dscam receptor may function as "zip-codes", which direct neurons to different addresses within the brain, giving the neuron specificity, says Dixon.

Further studies will search for signaling molecules that bind to different forms of Dscam and determine whether each version targets a unique area of the brain.

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Schmucker, D. et al. Drosophila Dscam is an axon guidance receptor exhibiting extraordinary molecular diversity. Cell 101, 671-684 (June 9, 2000).

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