Absence of ventral cell populations in the developing brain in a rat modelof the Smith-Lemli-Opitz syndrome

The Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive condition i nvolving craniofacial and central nervous system malformations with occasio nal holoprosencephaly (HPE). It is caused by a defect in the 7-dehydrochole sterol (7-DHC) reductase, the enzyme catalyzing the last step of cholestero l biosynthesis. Treatment of pregnant rats with inhibitors of 7-DHC reducta se, either AY9944 or BM15.766, has provided a valuable model to study the p athogenesis in SLOS, Recently, cholesterol has been shown to be involved in the posttranslational activation of the signaling protein Sonic Hedgehog, To identify the early defects associated with HPE in a rat model of SLOS, a nd to compare the phenotype of the treated embryos with that of the Shh(-/- ) mutants, we examined brain morphology and expression of three development al genes (Shh, Otx2, and Pax6) in 23-somite stage embryos from AY9944-treat ed dams, We report clearly abnormal morphology of the developing brain, con cerning primarily the ventral aspect of the neural tube. We observed a redu ced or absent expression of Shh and Otx2 in their ventral domain associated with extended ventral expression of Pax6. The results suggest an absence o f the midline ventral cell type at all levels of the cranial neural tube. T hey provide further evidence that cholesterol-deficiency-induced HPE origin ates from impaired Shh signaling activity in the ventral neural tube, Am. J , Med, Genet, 87:207-216, 1999, (C) 1999 Wiley-Liss, Inc.