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Gene-teratogen interactions influence the penetrance of birth defects by altering Hedgehog signaling strength.
Kong, Jennifer H; Young, Cullen B; Pusapati, Ganesh V; Espinoza, F Hernán; Patel, Chandni B; Beckert, Francis; Ho, Sebastian; Patel, Bhaven B; Gabriel, George C; Aravind, L; Bazan, J Fernando; Gunn, Teresa M; Lo, Cecilia W; Rohatgi, Rajat.
Afiliación
  • Kong JH; Departments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Young CB; Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15201, USA.
  • Pusapati GV; Departments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Espinoza FH; Departments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Patel CB; Departments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Beckert F; Departments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Ho S; Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15201, USA.
  • Patel BB; Departments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Gabriel GC; Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15201, USA.
  • Aravind L; National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA.
  • Bazan JF; H Bioconsulting, Stillwater, MN 50082, USA.
  • Gunn TM; McLaughlin Research Institute, Great Falls, MT 59405, USA.
  • Lo CW; Department of Developmental Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15201, USA.
  • Rohatgi R; Departments of Biochemistry and Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
Development ; 148(19)2021 10 01.
Article en En | MEDLINE | ID: mdl-34486668
Birth defects result from interactions between genetic and environmental factors, but the mechanisms remain poorly understood. We find that mutations and teratogens interact in predictable ways to cause birth defects by changing target cell sensitivity to Hedgehog (Hh) ligands. These interactions converge on a membrane protein complex, the MMM complex, that promotes degradation of the Hh transducer Smoothened (SMO). Deficiency of the MMM component MOSMO results in elevated SMO and increased Hh signaling, causing multiple birth defects. In utero exposure to a teratogen that directly inhibits SMO reduces the penetrance and expressivity of birth defects in Mosmo-/- embryos. Additionally, tissues that develop normally in Mosmo-/- embryos are refractory to the teratogen. Thus, changes in the abundance of the protein target of a teratogen can change birth defect outcomes by quantitative shifts in Hh signaling. Consequently, small molecules that re-calibrate signaling strength could be harnessed to rescue structural birth defects.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Anomalías Inducidas por Medicamentos / Penetrancia / Proteínas Hedgehog / Interacción Gen-Ambiente Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Development Asunto de la revista: BIOLOGIA / EMBRIOLOGIA Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Anomalías Inducidas por Medicamentos / Penetrancia / Proteínas Hedgehog / Interacción Gen-Ambiente Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Development Asunto de la revista: BIOLOGIA / EMBRIOLOGIA Año: 2021 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido