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In mice that lacked certain members of the endothelin family, neurons did not course down the external carotid artery, according to the team's findings. However, neurons grew down the internal carotid artery just fine, suggesting that endothelins beckon axons in one direction. The findings also support the idea that neurons use cues at various waypoints to navigate as opposed to taking a random path.
It's an “unexpected and exciting discovery” that endothelins, which work in the circulatory system, help guide certain neurons, says Tessier-Lavigne. Ginty is now looking for related molecules, such as those that guide neurons down the internal carotid artery.
Once neurons arrive at their destinations, they split into a tree of branches that cozy up to the target tissue and make their final connections. Several research groups are discovering the cues that guide this phase.
Branches of a single neuron rarely cross. A protein called DSCAM keeps dendrites from snarling, according to a trio of studies last year: one from HHMI investigators Lily Jan and Yuh Nung Jan of the University of California, San Francisco; one from HHMI investigator Lawrence Zipursky of the University of California, Los Angeles, who collaborated with Wesley Gruber (Yuh Nung Jan's former postdoctoral fellow); and a third from a team headed by Dietmar Schmucker (Zipursky's former postdoctoral fellow) of Harvard University.
Eight years ago, Zipursky and his colleagues found—to their surprise—that a single DSCAM gene could generate a huge number of subtly different variants of the protein—38,000 variations, in fact. Aside from the vertebrate immune system, which can generate a vast array of antibody proteins by shuffling single genes, getting such a large number of different proteins out of the same gene is unusual. Zipursky wondered if this extraordinary capability related to DSCAM's role in organizing neuron growth.
Test-tube experiments revealed that each variant binds to itself but not to other variants. Each neuron makes a random assortment of these variants and neighboring neurons are unlikely to make the same versions. Because dendrites from the same neuron would bear the same DSCAM variants, these molecules might allow the dendrites to recognize and grow away from each other, Zipursky proposed. Later experiments suggested that was the case.
In recent work, the three teams independently used Luo's MARCM technique to wipe out DSCAM in a small set of fly neurons. Dendrites of neurons lacking DSCAM frequently crossed, showing that the protein is required for them to avoid each other. DSCAM is made up of several parts, including one that protrudes inside the cell. Zipursky's team further showed that dendrites repel each other only when the protein bears this internal portion; without it, they cling together.
Photo: George Nikitin / AP, ©HHMI