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In vivo Perturb-Seq reveals neuronal and glial abnormalities associated with autism risk genes.
Jin, Xin; Simmons, Sean K; Guo, Amy; Shetty, Ashwin S; Ko, Michelle; Nguyen, Lan; Jokhi, Vahbiz; Robinson, Elise; Oyler, Paul; Curry, Nathan; Deangeli, Giulio; Lodato, Simona; Levin, Joshua Z; Regev, Aviv; Zhang, Feng; Arlotta, Paola.
Afiliación
  • Jin X; Society of Fellows, Harvard University, Cambridge, MA, USA. xinjin@fas.harvard.edu aregev@broadinstitute.org zhang@broadinstitute.org paola_arlotta@harvard.edu.
  • Simmons SK; Department of Stem Cell and Regenerative Biology, Harvard University, MA, USA.
  • Guo A; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Shetty AS; McGovern Institute of Brain Science, Department of Brain and Cognitive Science, Department of Biological Engineering, Massachussetts Institute of Technology (MIT), Cambridge, MA, USA.
  • Ko M; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Nguyen L; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Jokhi V; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Robinson E; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Oyler P; Department of Stem Cell and Regenerative Biology, Harvard University, MA, USA.
  • Curry N; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Deangeli G; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Lodato S; Department of Stem Cell and Regenerative Biology, Harvard University, MA, USA.
  • Levin JZ; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Regev A; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
  • Zhang F; Department of Stem Cell and Regenerative Biology, Harvard University, MA, USA.
  • Arlotta P; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Science ; 370(6520)2020 11 27.
Article en En | MEDLINE | ID: mdl-33243861
The number of disease risk genes and loci identified through human genetic studies far outstrips the capacity to systematically study their functions. We applied a scalable genetic screening approach, in vivo Perturb-Seq, to functionally evaluate 35 autism spectrum disorder/neurodevelopmental delay (ASD/ND) de novo loss-of-function risk genes. Using CRISPR-Cas9, we introduced frameshift mutations in these risk genes in pools, within the developing mouse brain in utero, followed by single-cell RNA-sequencing of perturbed cells in the postnatal brain. We identified cell type-specific and evolutionarily conserved gene modules from both neuronal and glial cell classes. Recurrent gene modules and cell types are affected across this cohort of perturbations, representing key cellular effects across sets of ASD/ND risk genes. In vivo Perturb-Seq allows us to investigate how diverse mutations affect cell types and states in the developing organism.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Trastorno Autístico / Encéfalo / Neuroglía / Neuronas Tipo de estudio: Etiology_studies / Prognostic_studies / Risk_factors_studies Límite: Animals / Humans Idioma: En Revista: Science Año: 2020 Tipo del documento: Article Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Trastorno Autístico / Encéfalo / Neuroglía / Neuronas Tipo de estudio: Etiology_studies / Prognostic_studies / Risk_factors_studies Límite: Animals / Humans Idioma: En Revista: Science Año: 2020 Tipo del documento: Article Pais de publicación: Estados Unidos