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When the zebrafish embryo is less than a day old, the parapineal nucleus begins forming from precursor cells that initially are symmetrical and located on both sides of the brain. At this point, Concha has determined, the two sides are essentially competing for the parapineal nucleus, but invariably the structure migrates over to the left side. It's like a tug-of-war that seems equal at the start but whose outcome is fixed so that the same team always wins. The asymmetry is now established, and the parapineal nucleus sends out a network of nerve fibers that contribute to left-sided asymmetry in the habenula as well.
The struggle for the nucleus is carried on via a "conversation" between cells on opposite sides of the zebrafish, Concha explains. In one experiment, he used a pinpoint laser to destroy cells on the left side, interrupting the dialogue. As a result, the parapineal nucleus randomly ended up on the left or the right side. So two separate genetic mechanisms have to be working for normal development—one directing the nucleus to form on one side only (asymmetry), and a second mechanism to ensure that the nucleus always takes its place on the same (left) side—laterality.
Concha and Wilson continue to collaborate in hunting for the genetic signals that enforce the left-leaning laterality of the zebrafish brain. Previously, they reported that the Nodal signaling pathway, known to be involved in regulating the left–right axis in embryos of a number of species, is more active on the left side of the zebrafish embryo and therefore seems to constitute a portion of the laterality-determining mechanisms. The question then becomes: What triggers Nodal activity on only one side? The issues continue to be teased apart, but Wilson admits they are "hellishly complicated." Or, as Columbia's Hobert says, "We are in the super-early days."
So how does this unbalanced brain affect the fish's behavior? Wilson, Concha, and others believe the neural asymmetry makes it possible for the animal's two eyes to have different, specialized functions. It was previously known that one eye scans the environment for novel stimuli such as predators, while the other pays attention to other zebrafish. Wilson's group found that when a zebrafish is trained to look into a mirror, it tends to use the same eye. Then they created mutants with reversed brain asymmetries—and the eye preferences were reversed as well. While this doesn't clinch the case, it is strong evidence supporting the structure-behavior connection. Moreover, it looks as if the lateral assignment of the functions is the same in all members of the species—a kind of organized behavioral specialization with survival implications.
In a similar quest, Hobert has turned to an even simpler model—C. elegans, the roundworm with a primitive nervous system made up of just 302 cells. This little worm has evolved a slight asymmetry to sharpen its detection of food-related chemical cues in the environment. In the C. elegans embryo, certain chemosensory nerve cells, called ASE neurons, are initially identical. By the time the worm has hatched, however, cells on the left side (ASEL) of the head region have expressed receptors that are sensitive to certain chemicals, while the neurons on the right (ASER) are tuned to different compounds.
"What that means is that asymmetry is derived," says Hobert, and it raises the question: How does "same" become "different?"
After generating hundreds of thousands of mutant C. elegans, Hobert and his colleagues discovered variants that lacked the asymmetry. These mutants had either left-sided neurons or right-sided neurons but not both, as in normal worms. These clues led the scientists to identify several molecular regulators that normally decide the fate of some ASE neurons to be "left" and others to be "right." In principle, it's much like the competitive process that Concha found in the zebrafish.