Beyond the Synapse: Convergence of Autism Risk Genes at the Cilium

PROJECT SUMMARY / ABSTRACT Autism spectrum disorder (ASD) is a relatively commonneurodevelopmental disorder (NDD), for which hundreds of large-effect risk genes have been identified. However, the molecular mechanisms underlying ASD remain unknown. ASD is commonly comorbid with disorders caused by cilia defects, but the possibility that cilia defects underlie ASD pathogenesis has not been systematically investigated. My dissertation work addresses this gap in knowledge by investigating the role of large-effect ASD risk genes in cilia formation using complementary model systems. To date, I have demonstrated that six high-confidence ASD risk genes localize to the cilium and are required for their formation, using both in vivo Xenopus models and in vitro human cells and transcriptomics. Included in these genes is the leading ASD risk gene, SYNGAP1, which has a canonical role in synaptic plasticity. My results show that it also plays a role earlier in brain development at the cilium, reframing its potential molecular contributions to ASD risk. The work proposed here will dissect the domains of SYNGAP1 necessary for its localization and function at the cilium using the high-throughput Xenopus model (Aim 1A). Then these findings will be translated to rodent models to dissect SYNGAP1 localization and function in a neural context, both at cellular and organ-level resolution using Syngap1 mutant rats (Aim 1B). To model human haploinsufficiency, we will complement this work by analyzing cilia phenotypes in SYNGAP1 patient iPSC- derived neurons (Aim 1C). Results from these studies will shift our understanding of the molecular mechanisms underlying ASD pathogenesis, particularly for the leading ASD risk gene SYNGAP1, with implications for other ‘synaptic’ ASD risk genes. This proposed work and training plan will prepare me for success in the K00 phase by providing technical training in advanced microscopy, image analysis, tissue processing, bioinformatics, and iPSC culture, as well as professional skills and intellectual experience in dissecting molecular mechanisms of NDDs. In Aim 2 (the K00 phase), I will continue to pursue my interests in understanding the molecular mechanisms of NDDs by investigating the role of lipids in the pathogenesis of NDDs. I will identify a postdoctoral laboratory that studies NDDs and can support my training in cutting-edge techniques in lipid biology, lipidomics, and transcriptomics while I develop professional, communication, and inclusive leadership skills. With the tools, professional skills, and technical skills I develop in the K00 phase, I will be well-positioned to start my independent research laboratory studying NDDs and create an inclusive environment to lead a diverse team of trainees and scientists.