The role of cholesterol in Shh signaling and teratogen-induced holoprosencephaly

Holoprosencephaly, or an undivided forebrain, is a complex brain malformati on associated with Sonic hedgehog (Shh) mutations. Other causes of holopros encephaly have converged upon the Shh signaling pathway: genetic and pharma cologic impair ment of cholesterol synthesis, and the action of the steroid al alkaloid cyclopamine. This review focuses on recent studies aimed at det ermining how Shh signaling is affected by these causes of holoprosencephaly , whether they involve a common mechanism and the role played by cholestero l. Cholesterol is potentially important for both biogenesis of Shh and in s ignal transduction in Shh-responsive cells. Teratogens that induce holopros encephaly appear to affect Shh signal transduction rather than Shh biogenes is. Analysis of these agents and other compounds that affect various aspect s of cellular cholesterol distribution indicates that the role of cholester ol in Shh signal transduction is novel and complicated. The similarity of t he Shh receptor, Patched (Ptc), to the Niemann-Pick Cl protein, which is in volved ill the vesicular trafficking of cholesterol, provides insight into the role of cholesterol and the action of compounds like cyclopamine.