title: Modeling Smith-Lemli-Opitz syndrome with induced pluripotent stem cells reveals a causal role for Wnt/β-catenin defects in neuronal cholesterol synthesis phenotypes.
abstract: Smith-Lemli-Opitz syndrome (SLOS) is a malformation disorder caused by mutations in DHCR7, which impair the reduction of 7-dehydrocholesterol (7DHC) to cholesterol. SLOS results in cognitive impairment, behavioral abnormalities and nervous system defects, though neither affected cell types nor impaired signaling pathways are fully understood. Whether 7DHC accumulation or cholesterol loss is primarily responsible for disease pathogenesis is also unclear. Using induced pluripotent stem cells (iPSCs) from subjects with SLOS, we identified cellular defects that lead to precocious neuronal specification within SLOS derived neural progenitors. We also demonstrated that 7DHC accumulation, not cholesterol deficiency, is critical for SLOS-associated defects. We further identified downregulation of Wnt/β-catenin signaling as a key initiator of aberrant SLOS iPSC differentiation through the direct inhibitory effects of 7DHC on the formation of an active Wnt receptor complex. Activation of canonical Wnt signaling prevented the neural phenotypes observed in SLOS iPSCs, suggesting that Wnt signaling may be a promising therapeutic target for SLOS.
authors.affiliation: Program in Genomics of Differentiation, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH), Bethesda, Maryland, USA.|Program in Developmental Endocrinology and Genetics, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, Maryland, USA.
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Francis
authors.affiliation: Program in Genomics of Differentiation, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors.forename: Amy N
authors.initials: AN
authors.lastname: Ton
authors.affiliation: Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Yao
authors.initials: Y
authors.lastname: Xin
authors.affiliation: Program in Genomics of Differentiation, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors.forename: Peter E
authors.initials: PE
authors.lastname: O'Halloran
authors.affiliation: Program in Developmental Endocrinology and Genetics, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, Maryland, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Wassif
authors.affiliation: Program in Genomics of Differentiation, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors.forename: Nasir
authors.initials: N
authors.lastname: Malik
authors.affiliation: Program in Developmental Endocrinology and Genetics, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, Maryland, USA.
authors.forename: Ian M
authors.initials: IM
authors.lastname: Williams
authors.affiliation: Program in Developmental Endocrinology and Genetics, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, Maryland, USA.
authors.forename: Celine V
authors.initials: CV
authors.lastname: Cluzeau
authors.affiliation: Computational and Statistical Genomics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA.
authors.forename: Niraj S
authors.initials: NS
authors.lastname: Trivedi
authors.affiliation: Genetic Diseases Research Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Pavan
authors.affiliation: Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois, USA.
authors.forename: Wonhwa
authors.initials: W
authors.lastname: Cho
authors.affiliation: Program in Genomics of Differentiation, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH), Bethesda, Maryland, USA.
authors.forename: Heiner
authors.initials: H
authors.lastname: Westphal
authors.affiliation: Program in Developmental Endocrinology and Genetics, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, Maryland, USA.
authors.forename: Forbes D
authors.initials: FD
authors.lastname: Porter
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D002784:Cholesterol / Q000096:biosynthesis / Q000378:metabolism; D003684:Dehydrocholesterols / Q000378:metabolism; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism* / Q000637:transplantation; D051379:Mice; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics / Q000378:metabolism; D019082:Smith-Lemli-Opitz Syndrome / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D060449:Wnt Signaling Pathway / Q000235:genetics*
chemical_list: D003684:Dehydrocholesterols; D002784:Cholesterol; C016705:7-dehydrocholesterol; D044925:Oxidoreductases Acting on CH-CH Group Donors; C019995:7-dehydrocholesterol reductase