DSCAM also exists in mice, and a study earlier this year revealed that it might carry out a similar function: mice without it have neurons that clump and don't spread. “The molecule used for self-avoidance seems to have been conserved,” says Yuh Nung Jan. But the mammalian version of DSCAM doesn't come in the plethora of flavors that the fly version does, and how rodent neurons establish independent identities remains to be seen.

Many other important questions also remain, says Zipursky. Is DSCAM's sole job to tell a neuron to avoid itself or does it carry out other tasks too? Do cells always use a random assortment of DSCAMs or do particular variants identify subsets of neurons? To investigate those questions, his group is generating flies that are missing specific sets of DSCAM variants.

To make connections correctly, neurons also need signals from skin, muscle, or other tissues they ultimately connect to. Ginty knew that such target tissues release a molecule called NGF, or nerve growth factor, which prompts certain kinds of neurons to branch and supports their survival. He then found that neurons exposed to NGF ramp up production of a gene-controlling molecule called SRF. Further genetic studies revealed that SRF relays NGF's order for a neuron to branch and penetrate the target tissue. However, SRF is not necessary to communicate NGF's survival message—without SRF, neurons exposed to NGF survive. Some other molecules must prevent cells from dying.

The role of SRF is intriguing, says Ginty, because the molecule exists only in a neuron's nucleus—not in its growing tip, where the neuron first encounters NGF. He is keen to understand how NGF communicates with the nucleus. In Ginty's preferred model, the cell membrane at the neuron's end pinches off, forming small spheres that capture NGF and transport the growth factor along with its receptor all the way back to the cell body, where the nucleus resides. The model makes sense because defects in this transport system are implicated in neurodegenerative disorders such as Parkinson's disease and amyotrophic lateral sclerosis, or ALS (often referred to as Lou Gehrig's disease).

What is remarkable, says Ginty, is that NGF influences an axon's growth and branching by tweaking genes in the cell's nucleus. Because cells see NGF at their growing end, “it wasn't intuitive that you'd need signaling all the way to the nucleus.” One reason for such an ornate process might be that neurons must shift modes. “Until it reaches the target region, the role of a neuron is to grow, grow, grow,” he says. But once it arrives, it must penetrate the tissue, branch, and form connections. NGF might be the trigger that tells the neuron to switch on all the genes required to perform the new gymnastics.

Ginty's work is also defining how sets of connections involving many neurons are fine-tuned. As an organism establishes its nervous system, it sends more neurons than necessary to a particular place. Ginty and his team have found that neurons use a series of genetic feedback loops to determine which cells live and which ones die. As a result, when a group of neurons see NGF, some of them become more sensitive to the molecule and consequently become robust survivors, Ginty and his colleagues reported in the April 18, 2008, issue of Science.

In addition, the hearty cells churn out molecules that kill off neighboring neurons. Those neighbors see NGF, but the death molecules appear to override the NGF signal. The right balance between the forces that make neurons strong and those that kill them helps an organism wire up just the right number of connections.

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