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Jumbled Organs Lead to One-Sided Discovery

Though an unfertilized egg starts out as a uniform sphere, a vertebrate embryo's genes rapidly go to work to make its head different from its tail, its front different from its back, and--when it comes to internal organs such as the heart, liver, and lungs--its left side different from its right. Scientists already have a basic picture of the machinery that creates head-tail and front-back differences. Now, by studying bizarre cases of mice and people whose organs are reversed or jumbled, two research teams have discovered important new clues to why our left side is not a carbon copy of our right.

One key player may be a "motor" protein that shuttles molecular signals through a cell's cytoplasm, Yale University pediatric cardiologist Martina Brueckner and colleagues report in the 30 October issue of Nature. Brueckner's group looked for gene defects in two strains of mice with situs inversus, a mutation in which the heart, lungs, and other organs are inverted, like a mirror image. The team found changes in a gene encoding a previously unknown "dynein," a protein that moves like a railroad locomotive along cytoskeletal fibers called microtubules, hauling other molecules as cargo.

Microtubules, Brueckner points out, "are inherently asymmetric structures," with positive and negative ends that determine the direction a dynein may travel. Indeed, the group found that the affected gene, named left-right dynein (lrd), comes on in the "node"--a key source of patterning signals--just before the appearance in the mouse embryo of the first known left-right asymmetries, the left-sided expression of two genes called nodal and lefty. That suggests that the dynein's job could be either to drag molecular signals that activate lefty or nodal to the node's left side, or to carry signals that repress them to the right side, says Joseph Yost, a developmental biologist at the University of Utah in Salt Lake City. "The big questions now are, what is this dynein moving around, and how do the microtubules get oriented?" he says.

One of those questions may already have been answered, thanks to work reported by geneticist Brett Casey of Baylor College of Medicine in Houston and colleagues in the November issue of Nature Genetics. Casey's group studied human families with multiple cases of situs inversus, which is usually harmless, or situs ambiguus, a much more dangerous condition in which the internal organs are scattered randomly. Affected family members, the group found, had inherited one or two defective copies of ZIC3, a previously unknown gene that appears to code for a transcription factor--a protein that switches other genes on or off.

The two studies suggest a tantalizing possibility, Casey says. "It's long been my hunch that the earliest events in left-right asymmetry involve a shunting [of signaling proteins such as ZIC3] to one side or the other, and it's certainly appealing to invoke dyneins and the cytoskeleton to help with that," says Casey. Nailing the genes that misfire in left-right disorders such as situs ambiguus, Casey notes, may eventually help scientists provide genetic counseling to prospective parents who carry the mutations.