title: The role of cholesterol in Shh signaling and teratogen-induced holoprosencephaly.
abstract: Holoprosencephaly, or an undivided forebrain, is a complex brain malformation associated with Sonic hedgehog (Shh) mutations. Other causes of holoprosencephaly have converged upon the Shh signaling pathway: genetic and pharmacologic impairment of cholesterol synthesis, and the action of the steroidal alkaloid cyclopamine. This review focuses on recent studies aimed at determining how Shh signaling is affected by these causes of holoprosencephaly, whether they involve a common mechanism and the role played by cholesterol. Cholesterol is potentially important for both biogenesis of Shh and in signal transduction in Shh-responsive cells. Teratogens that induce holoprosencephaly appear to affect Shh signal transduction rather than Shh biogenesis. Analysis of these agents and other compounds that affect various aspects of cellular cholesterol distribution indicates that the role of cholesterol in Shh signal transduction is novel and complicated. The similarity of the Shh receptor, Patched (Ptc), to the Niemann-Pick Cl protein, which is involved in the vesicular trafficking of cholesterol, provides insight into the role of cholesterol and the action of compounds like cyclopamine.
authors.affiliation: Department of Biological Structure and Center for Developmental Biology, University of Washington, Seattle 98195, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Incardona
authors.forename: H
authors.initials: H
authors.lastname: Roelink
mesh_terms: D000818:Animals; D001693:Biological Transport, Active; D002352:Carrier Proteins; D002784:Cholesterol / Q000502:physiology*; D053823:Hedgehog Proteins; D016142:Holoprosencephaly / Q000209:etiology* / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins / Q000502:physiology; D008954:Models, Biological; D009154:Mutation; D000077296:Niemann-Pick C1 Protein; D000072079:Patched Receptors; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D011956:Receptors, Cell Surface; D015398:Signal Transduction / Q000187:drug effects; D013723:Teratogens / Q000633:toxicity; D015534:Trans-Activators; D014704:Veratrum Alkaloids / Q000494:pharmacology; D001371:trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride / Q000494:pharmacology
chemical_list: D002352:Carrier Proteins; D053823:Hedgehog Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein; D000072079:Patched Receptors; D011506:Proteins; D011956:Receptors, Cell Surface; C509239:SHH protein, human; D013723:Teratogens; D015534:Trans-Activators; D014704:Veratrum Alkaloids; D001371:trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride; D002784:Cholesterol; C000541:cyclopamine