Nature Genetics
33, 508 - 513 (2003)
Published online: 24 March 2003; | doi:10.1038/ng1134
There is a Corrigendum (May 2003) associated with this Letter.
A defective response to Hedgehog signaling in disorders of cholesterol biosynthesisMichael K. Cooper1, 2, 5, Christopher A. Wassif3, Patrycja A. Krakowiak3, Jussi Taipale1, Ruoyu Gong1, Richard I. Kelley4, Forbes D. Porter3
& Philip A. Beachy11
Department of Molecular Biology and Genetics, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. 2
Department of Neurology, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. 3
Heritable Disorders Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-1830, USA. 4
Kennedy Krieger Institute, Baltimore, Maryland 21205, USA. 5
Present address: Department of Neurology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA.
Correspondence should be addressed to Philip A. Beachy pbeachy@jhmi.eduSmith−Lemli−Opitz syndrome (SLOS), desmosterolosis and lathosterolosis are human syndromes caused by defects in the final stages of cholesterol biosynthesis. Many of the developmental malformations in these syndromes occur in tissues and structures whose embryonic patterning depends on signaling by the Hedgehog (Hh) family of secreted proteins. Here we report that response to the Hh signal is compromised in mutant cells from mouse models of SLOS and lathosterolosis and in normal cells pharmacologically depleted of sterols. We show that decreasing levels of cellular sterols correlate with diminishing responsiveness to the Hh signal. This diminished response occurs at sterol levels sufficient for normal autoprocessing of Hh protein, which requires cholesterol as cofactor and covalent adduct. We further find that sterol depletion affects the activity of Smoothened (Smo), an essential component of the Hh signal transduction apparatus.
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