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Using MARCM, Luo has investigated how olfactory neurons and projection neurons find each other during development of the fly brain. “It's like 50 men and 50 women on a dance floor, each needing to find dancing partners,” he says. His team has found that the dance floor isn't mapped out before the neurons get there. Instead, one partner—a projection neuron—sets up where each match will take place. Then olfactory neurons come in and find the right partner. Luo and his colleagues have discovered many of the guidelines for accomplishing this quest. Neurons seem to divide up the problem. First, one set of molecular cues directs neurons to the general vicinity, like a dancer looking for a partner near the bandstand and ignoring the rest of the room. Then, another set of cues helps neurons move systematically from cell to cell in the vicinity until finding the exact meeting spot.
Luo and his team are also mapping how projection neurons connect olfactory neurons with other parts of the brain. They mark projection neurons that link to particular olfactory receptor neurons and then take snapshots of fly brains with those neurons lit up. So far they've mapped 35 of the 50 types of fly olfactory receptors. They now want to overlay the maps of different neuron types, but each brain is subtly different from another in the size and arrangement of its parts. So they use computer programs to align each image with a “master brain,” from which they are creating a unified map of the fly's olfactory system.
Luo knows whether a particular olfactory receptor detects, for example, fruit (the fly's food source) or pheromones (chemicals one individual emits to spur behaviors, such as mating, in another). As a result, the map illuminates not just where neurons go but what kind of smell information each one communicates. The method has already yielded important findings. Neurons that detect signals related to fruit cluster on one side of the lateral horn, a brain center for interpreting smell data, Luo's team reported in March 2007 in Cell. Neurons that twitter in response to pheromones cluster on the other side of the lateral horn.
“You have a special fruit-processing area and a special pheromone-processing area,” says Luo. “From our mapping, this becomes very clear.” According to the smells that neurons sense, the cells separate into areas that control different biological functions. Presumably, other neurons use information from the “fruit area” to spur the fly to eat or information from the “pheromone area” to tell the fly to start a courtship dance.
Researchers also want to understand how neurons decide to change direction at waypoints during the developmental journey. David D. Ginty, an HHMI investigator at Johns Hopkins University, is studying the mouse to examine a set of neurons whose axons travel along arteries away from the spinal cord to the face. At one point, these projections hit a fork in the road: one group of axons follows the external carotid artery to the salivary glands, while another meanders along the internal carotid artery bound for the eye, pineal glands, and other destinations.
Something must tell the axons to go one way or the other. To identify possible signals, Ginty and his team extracted bits of each of the arteries and looked for genes activated in the external carotid artery, but not in the internal carotid artery; they pinpointed particular genes that encode members of the endothelin protein family. Although this group of molecules is involved in regulating blood pressure, the finding that more of the molecules appeared in one artery than in the other suggested that the proteins might direct axons down the external carotid artery, the researchers reported in the April 2008 issue of Nature.
Photo: Jennifer Bishop