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

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Abstract
Asymmetric expression of Sonic hedgehog ( Shh ) in Hensen’s node of the chicken embryo plays a key role in the genetic cascade that controls left-right asymmetry, but its involvement in left-right specification in other vertebrates remains unclear. We show that mouse embryos lacking Shh display a variety of laterality defects, including pulmonary left isomerism, alterations of heart looping, and randomization of axial turning. Expression of the left-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 pathway 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 vertebrates, and the Shh and RA pathways converge in the control of Lefty-1 .