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Dividing an organism into unequal halves just took a giant step backward—in time, that is. Michael Levin, Mark Mercola (Harvard Medical School, Boston, MA), and colleagues have identified what is so far the earliest-acting determinant of left/right (LR) asymmetry. According to their findings, this early determinant establishes voltage differences that distinguish left from right.

Based on previous evidence that gap junctions are required for LR asymmetry, the group devised a simple model to explain how asymmetry determinants might be driven directionally through gap junctions in a process akin to electrophoresis. Though he did not necessarily believe the model, Mercola says, “the idea that voltage differences and channels or pumps may be important was testable.”

And tested it was. In what Mercola likes to call the Sigma catalogue screen, the authors threw hundreds of ion flux inhibitors at developing frog embryos. Many of the chemicals that disrupted LR asymmetry (e.g., caused the normally left-lying heart to be situated on the right) displayed a common attribute: they influenced potassium transport into or out of the cell. More specific compounds revealed that inhibiting the H⁺/K⁺ ATPase transporter upset asymmetric gene expression patterns known to dictate the hemisphere in which organs form.

The H⁺/K⁺ ATPase is the first determinant found upstream of the asymmetric gene expression cascade. In frogs, LR asymmetry was set as early as the two-cell stage, at which point the H⁺/K⁺ ATPase mRNA was often already asymmetrically localized near the point of cell–cell contact. The H⁺/K⁺ ATPase mRNA was not asymmetric in chick embryos, but the pump did establish a voltage difference between cells on opposite sides of the primitive streak.

It is still unclear how the pump affects downstream gene expression. Transporter activity on one side of the embryo or streak could make the cell interior more negatively charged, and thus could drive an electrophoresis effect between cells. But, to support their electrophoresis model, Mercola must determine whether the cells affected by the ATPase are the cells linked by the asymmetry-promoting gap junctions. Alternatively, the pump may directly regulate some factor that leads to asymmetry. ▪

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