Telling left from right in chick embryos.

The left and right halves of an embryo in its earliest stages of development may look perfectly balanced, but on a molecular level its genes are already choosing sides.

Researchers have found that certain proteins are made on either the left or the right side of the embryo, marking the first few steps in a molecular pathway that determines left-right asymmetry in the adult animal.

Cliff Tabin of Harvard Medical School in Boston and his colleagues report in the Sept. 8 Cell their discovery that proteins from three genes--activin receptor IIa (cAct-RIIa), sonic hedgehog (Shh), and chicken nodal-related 1 (cNR-1)--form a sort of two-pronged biochemical cascade. On the left side, the Shh protein spurs cNR-1 protein synthesis, while on the right side, a molecule called activin suppresses synthesis of Shh and stimulates production of cAct-RIIa.

The researchers knew that these genes influence a wide range of developmental events, which amplifies the importance of their discovery of different protein pathways on the two sides, Tabin says. The genes' functions "made it seem plausible that these things were involved in controlling asymmetry," he says.

This idea held up when the group manipulated protein synthesis to see how it affected development of the chick embryo's heart. When they stimulated Shh production on both sides, not just the left, they saw that the newly formed heart tubes--which usually loop to the right--opted to curl to the left half of the time. The 50-50 pattern was consistent with the heart tube's receiving signals from both the left and right sides, essentially leaving the direction of its growth to chance. Moreover, suppressing Shh production on both sides gave the same results.

Further work in this area could include finding additional steps in the pathway, determining the signals that actually make the heart tube bend, and measuring how far the signals travel from their source, Tabin says.