PT - JOURNAL ARTICLE AU - Marcella Birtele AU - Ashley Del Dosso AU - Tiantian Xu AU - Tuan Nguyen AU - Brent Wilkinson AU - Jean-Paul Urenda AU - Gavin Knight AU - Roger Moore AU - Ritin Sharma AU - Patrick Pirrotte AU - Randolph S. Ashton AU - Eric J. Huang AU - Marcelo P. Coba AU - Giorgia Quadrato TI - The autism-associated gene SYNGAP1 regulates human cortical neurogenesis AID - 10.1101/2022.05.10.491244 DP - 2022 Jan 01 TA - bioRxiv PG - 2022.05.10.491244 4099 - http://biorxiv.org/content/early/2022/05/10/2022.05.10.491244.short 4100 - http://biorxiv.org/content/early/2022/05/10/2022.05.10.491244.full AB - Autism spectrum disorder (ASD) is a genetically heterogeneous disorder linked with rare, inherited and de novo mutations occurring in two main functional gene categories: gene expression regulation and synaptic function1. Accumulating evidence points to dysregulation in cortical neurogenesis as a convergent mechanism in ASD pathophysiology2–8. While asynchronous development has been identified as a shared feature among ASD-risk genes in the category of gene expression regulation, it remains unknown whether this phenotype is also associated with ASD-risk genes in the synaptic function category. Here we show for the first time the expression of the synaptic Ras GTP-ase activating protein 1 (SYNGAP1), one of the top ASD risk genes9, in human cortical progenitors (hCPs). Interestingly, we found that multiple components of the postsynaptic density (PSD) of excitatory synapses, of which SYNGAP1 is one of the most abundant components 10,11, are enriched in the proteome of hCPs. Specifically, we discover that SYNGAP1 is expressed within the apical domain of human radial glia cells (hRGCs) where it lines the wall of the developing cortical ventricular zone colocalizing with the tight junction-associated protein and MAGUK family member TJP1. In a cortical organoid model of SYNGAP1 haploinsufficiency, we show dysregulated cytoskeletal dynamics that impair the scaffolding and division plane of hRGCs, resulting in disrupted lamination of the cortical plate and accelerated maturation of cortical projection neurons. Overall, the dual function of SYNGAP1 in neuronal synapses and progenitor cells reframes our understanding of the pathophysiology of SYNGAP1-related disorders and, more broadly, underscores the importance of dissecting the role of synaptic genes associated with neurodevelopmental disorders in distinct cell types across developmental stages.Competing Interest StatementG.K. and R.S.A are inventors on U.S. Patent App. No. 16/044236 that describes methods for generating microarrayed single rosette cultures, and they are co-founders of Neurosetta LLC that is focused on commercializing the culture platform.