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Non-synaptic function of the autism spectrum disorder-associated gene SYNGAP1 in cortical neurogenesis.
Birtele, Marcella; Del Dosso, Ashley; Xu, Tiantian; Nguyen, Tuan; Wilkinson, Brent; Hosseini, Negar; Nguyen, Sarah; Urenda, Jean-Paul; Knight, Gavin; Rojas, Camilo; Flores, Ilse; Atamian, Alexander; Moore, Roger; Sharma, Ritin; Pirrotte, Patrick; Ashton, Randolph S; Huang, Eric J; Rumbaugh, Gavin; Coba, Marcelo P; Quadrato, Giorgia.
Afiliação
  • Birtele M; Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Del Dosso A; 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.
  • Nguyen T; 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 Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Hosseini N; 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; Xiangya Hospital, Central South University, Changsha, China.
  • Urenda JP; Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Knight G; 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.
  • Rojas C; Department of Psychiatry and Behavioral Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Flores I; 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.
  • Moore R; 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.
  • Sharma R; Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Pirrotte P; 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.
  • Ashton RS; Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
  • Huang EJ; 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.
  • Rumbaugh G; Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI, USA.
  • Coba MP; Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI, USA.
  • Quadrato G; Departments of Neuroscience and Molecular Medicine, University of Florida Scripps Biomedical Research Institute, Jupiter, FL, USA.
Nat Neurosci ; 26(12): 2090-2103, 2023 Dec.
Article em En | MEDLINE | ID: mdl-37946050
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Transtornos do Neurodesenvolvimento / Transtorno do Espectro Autista Limite: Animals / Humans Idioma: En Revista: Nat Neurosci Assunto da revista: NEUROLOGIA Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Transtornos do Neurodesenvolvimento / Transtorno do Espectro Autista Limite: Animals / Humans Idioma: En Revista: Nat Neurosci Assunto da revista: NEUROLOGIA Ano de publicação: 2023 Tipo de documento: Article País de afiliação: Estados Unidos