Non-synaptic function of the autism spectrum disorder-associated gene SYNGAP1 in cortical neurogenesis.

Autor:	Birtele M; Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Del Dosso A; Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Xu T; Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.; Xiangya Hospital, Central South University, Changsha, China., Nguyen T; Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Wilkinson B; Department of Psychiatry and Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.; Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Hosseini N; Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Nguyen S; Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Urenda JP; Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Knight G; Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, USA.; Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI, USA., Rojas C; Departments of Neuroscience and Molecular Medicine, University of Florida Scripps Biomedical Research Institute, Jupiter, FL, USA.; Skaggs Graduate School of Chemical and Biological Sciences, Scripps Research, Jupiter, FL, USA., Flores I; Department of Psychiatry and Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.; Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Atamian A; Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Moore R; Integrated Mass Spectrometry Shared Resource, City of Hope Comprehensive Cancer Center, Duarte, CA, USA., Sharma R; Integrated Mass Spectrometry Shared Resource, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.; Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ, USA., Pirrotte P; Integrated Mass Spectrometry Shared Resource, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.; Cancer and Cell Biology Division, Translational Genomics Research Institute, Phoenix, AZ, USA., Ashton RS; Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, USA.; Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI, USA., Huang EJ; Department of Pathology, University of California, San Francisco, CA, USA.; Eli and Edythe Broad Institute for Stem Cell Research and Regeneration Medicine, University of California, San Francisco, CA, USA., Rumbaugh G; Departments of Neuroscience and Molecular Medicine, University of Florida Scripps Biomedical Research Institute, Jupiter, FL, USA.; Skaggs Graduate School of Chemical and Biological Sciences, Scripps Research, Jupiter, FL, USA., Coba MP; Department of Psychiatry and Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.; Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.; Department of Physiology and Neuroscience, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA., Quadrato G; Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. quadrato@usc.edu.; Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research at USC, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. quadrato@usc.edu.
Jazyk:	angličtina
Zdroj:	Nature neuroscience [Nat Neurosci] 2023 Dec; Vol. 26 (12), pp. 2090-2103. Date of Electronic Publication: 2023 Nov 09.
DOI:	10.1038/s41593-023-01477-3
Abstrakt:	Genes involved in synaptic function are enriched among those with autism spectrum disorder (ASD)-associated rare genetic variants. Dysregulated cortical neurogenesis has been implicated as a convergent mechanism in ASD pathophysiology, yet it remains unknown how 'synaptic' ASD risk genes contribute to these phenotypes, which arise before synaptogenesis. Here, we show that the synaptic Ras GTPase-activating (RASGAP) protein 1 (SYNGAP1, a top ASD risk gene) is expressed within the apical domain of human radial glia cells (hRGCs). In a human cortical organoid model of SYNGAP1 haploinsufficiency, we find dysregulated cytoskeletal dynamics that impair the scaffolding and division plane of hRGCs, resulting in disrupted lamination and accelerated maturation of cortical projection neurons. Additionally, we confirmed an imbalance in the ratio of progenitors to neurons in a mouse model of Syngap1 haploinsufficiency. Thus, SYNGAP1-related brain disorders may arise through non-synaptic mechanisms, highlighting the need to study genes associated with neurodevelopmental disorders (NDDs) in diverse human cell types and developmental stages. (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze:	MEDLINE
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