Multiple left-right asymmetry defects in Shh(-/-) mutant mice unveil a convergence of the Shh and retinoic acid pathways in the control of Lefty-1

Asymmetric expression of Sonic hedgehog (Shh) in Hensen's node of the chick en embryo plays a key role in the genetic cascade that controls left-right asymmetry, but its involvement in left-right specification in other vertebr ates remains unclear. We show that mouse embryos lacking Shh display a vari ety of laterality defects, including pulmonary left isomerism, alterations of heart looping, and randomization of axial turning. Expression of the lef t-specific gene Lefty-1 is absent in Shh(-/-) embryos, suggesting that the observed laterality defects could be the result of the lack of Lefty-1. We also demonstrate that retinoic acid (RA) controls Lefty-1 expression in a p athway downstream or parallel to Shh. Further, we provide evidence that RA controls left-right development across vertebrate species. Thus, the roles of Shh and RA in left-right specification indeed are conserved among verteb rates, and the Shh and RA pathways converge in the control of Lefty-1.