Analysis of Nsdhl-deficient embryos reveals a role for Hedgehog signaling in early placental development.

[child syndrome]

The X-linked Nsdhl gene encodes a sterol dehydrogenase involved in cholesterol biosynthesis . Mutations in this gene cause the male lethal phenotypes in human CHILD syndrome and bare patches (Bpa ) mice . Affected male embryos for several mutant Nsdhl alleles die in mid-gestation with a thin and poorly vascularized placental labyrinth . The timing and specific abnormalities noted suggest a defect in one or more developmental signaling pathways as a possible mechanism . Here , we examined the possible involvement of the hedgehog signaling pathway in the placental pathology of Nsdhl mutants using a transgenic mouse line (Ptch 1 (tm 1 Mps )) that contains a lacZ reporter under the control of the promoter for Ptch 1 , the gene that encodes the major hedgehog receptor . We demonstrate expression of Ptch 1 in allantoic mesoderm of the placenta from wild-type mid-gestation embryos . The evidence suggests that the signaling is induced by Indian hedgehog that is produced by distal (ectoplacental ) visceral endoderm cells that migrate into the allantoic mesoderm before embryonic day 10 .0 . Using a ubiquitously expressed , X-linked lacZ transgene that undergoes normal X-inactivation , we demonstrate that the placental defects in Nsdhl /+ female embryos are non-cell autonomous . Further , affected placentas from mutant Nsdhl (Bpa-8 H ) male embryos demonstrate markedly decreased or no Ptch 1 -lacZ staining and no migration of Ihh expressing cells into the developing placenta . These data strongly implicate the hedgehog signaling pathway in the pathogenesis of the placental defects in NSDHL deficiency and provide evidence for a role for the hedgehog pathway in the development of a functional mammalian placenta .