# The Role of the ASD Risk Gene CHD8 in Neural Development

> **NIH NIH F30** · YALE UNIVERSITY · 2024 · $33,892

## Abstract

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...

## Key facts

- **NIH application ID:** 10906033
- **Project number:** 5F30MH132282-03
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Sarah E. Fitzpatrick
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $33,892
- **Award type:** 5
- **Project period:** 2022-09-16 → 2026-09-15

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10906033

## Citation

> US National Institutes of Health, RePORTER application 10906033, The Role of the ASD Risk Gene CHD8 in Neural Development (5F30MH132282-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10906033. Licensed CC0.

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