# The molecular roles of RFX3 in neurodevelopment and Autism Spectrum disorder

> **NIH NIH F30** · HARVARD MEDICAL SCHOOL · 2022 · $39,014

## Abstract

Project Abstract
Autism Spectrum Disorder (ASD) is the most common neurodevelopmental disorder, yet the
neurobiological mechanisms underlying ASD pathogenesis remain largely unknown. Large-scale
exome sequencing studies of individuals with ASD have identified over 100 genes significantly
associated with ASD risk. Functional characterization of ASD risk genes can provide insight to
ASD pathogenesis. We and others have recently identified de novo loss-of-function variants in
the transcription factor RFX3 as a relatively common monogenic cause of ASD, implying an
important role for RFX3 in human neurodevelopment. We have found evidence that RFX3 may
be a critical transcriptional regulator of the development and function of layer II/III neurons: its
expression is significantly enriched in cortical layer II/III excitatory neurons, and the RFX3 binding
motif is specifically enriched in accessible chromatin regions of the human fetal germinal zone
and layer II/III excitatory neurons. In this proposed research, I will address the hypothesis that
RFX3 regulates key neurodevelopmental processes in layer II/III excitatory neurons and the
expression of other ASD risk genes that affect neuronal formation and function. In Aim 1, I will
identify the genes and pathways regulated by RFX3 in human cortical neurons by profiling the
genome-wide binding sites of RFX3 and the transcriptional changes induced by loss of RFX3
occupancy in RFX3 haploinsufficient human iPSC-derived neurons. In Aim 2, I will evaluate the
effect of RFX3 haploinsufficiency on cortical neuron formation and synaptic function in human
iPSC-derived forebrain organoids. I will use single-cell RNA-sequencing to identify changes in cell
type composition and infer alterations in developmental trajectories in RFX3 deficient organoids,
and multielectrode array to assess synaptic plasticity balance in RFX3 deficient organoids
compared to isogenic controls. Taken together, this proposal will yield insight on the
transcriptional programs regulated by RFX3 in human neurons, and how RFX3 haploinsufficiency
disrupts neuronal development and function. This will allow for improved understanding of ASD
neurobiology, and the development of novel targeted therapies for ASD.

## Key facts

- **NIH application ID:** 10535366
- **Project number:** 1F30MH128995-01A1
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** Jenny Lai
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $39,014
- **Award type:** 1
- **Project period:** 2022-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10535366

## Citation

> US National Institutes of Health, RePORTER application 10535366, The molecular roles of RFX3 in neurodevelopment and Autism Spectrum disorder (1F30MH128995-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10535366. Licensed CC0.

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