The Role of the ASD Risk Gene CHD8 in Neural Development

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Autism spectrum disorder (ASD) refers to a group of neurodevelopmental conditions characterized by impairments in social skills, verbal and nonverbal communication, and repetitive behaviors. ASD is highly prevalent, affecting up to 1 in 44 children in the United States and has been studied for decades, yet the underlying neural mechanisms that lead to the disorder are poorly understood. No biological tests to diagnose ASD earlier nor treatments targeting the core symptoms of ASD are available. Identification and functional analyses of high-confidence ASD risk genes are beginning to uncover convergent pathways by which genes with diverse functions lead to ASD. De novo mutations in Chromodomain Helicase DNA Binding Protein 8 (CHD8) are among the most strongly associated with ASD. CHD8 encodes a chromatin modifier that affects cell cycle progression through its role in gene expression regulation. Cell cycle control affects the timing of neural progenitor cell (NPC) proliferation and differentiation into neurons, which lays the foundation for proper neurodevelopment. Although numerous studies to date have improved our insight into CHD8 function, there are still critical gaps in our understanding of how CHD8 mutation alters cell cycle progression and neural proliferation, when these alterations take place, and the molecular mechanisms underlying these changes. To address these gaps, I will use a zebrafish line with a loss-of-function mutation in chd8. Zebrafish provide key advantages for studying early neurodevelopment processes in ways not feasible with mouse or in vitro models. Neural proliferation and migration take place from ~14 to 96 hours post-fertilization (hpf), providing easy access to embryonic timepoints that are difficult to study in mice. This vertebrate system will allow us to directly study fundamental neurodevelopmental processes at cellular, transcriptional, and circuit levels at critical time points, which is essential for understanding the function of CHD8 in shaping the developing brain. Based on my preliminary data, I hypothesize that CHD8 mutation causes decreased expression of proteins involved in translation initiation and cell cycle phase transitions, resulting in altered cell cycle timing and neural proliferation and differentiation, which may ultimately affect synaptogenesis and circuit formation. Aim 1 will investigate how and when mutations in CHD8 affect cell cycle timing and the balance of NPC proliferation and differentiation across early vertebrate neurodevelopment in vivo. Aim 2 will investigate the mechanisms underlying changes in cell cycle progression by investigating the impact of CHD8 mutations on protein synthesis. Together, my research will use rigorous multi-level approaches to elucidate the role of CHD8 in neurodevelopmental cell cycle regulation and protein synthesis, which will advance our understanding of ASD neurobiology. In addition to learning technical approaches in a powerful model system that will provide me with rigorous scientific training, my training plan affords me numerous growth opportunities with the support of superb mentors to pursue my long-term goal of becoming an independent physician-scientist.