학술논문
Non-synaptic function of the autism spectrum disorder-associated gene SYNGAP1in cortical neurogenesis
Document Type
Article
Author
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
Source
Nature Neuroscience; December 2023, Vol. 26 Issue: 12 p2090-2103, 14p
Subject
Language
ISSN
10976256; 15461726
Abstract
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 SYNGAP1haploinsufficiency, 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 Syngap1haploinsufficiency. 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.