# SIGNAL TRANSDUCTION PATHWAYS REGULATING NEURON DIFFERENTIATION

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2022 · $577,776

## Abstract

The long-term goals of the proposed research are to elucidate the epigenetic mechanisms that control
neuronal connectivity in the brain. We have recently discovered essential roles for the chromatin remodeling
enzyme Chd4 in granule neuron connectivity in the mouse cerebellum. Strikingly, genome-wide analyses of the
cerebellum in conditional Chd4 knockout mice reveal that Chd4 triggers deposition of the histone variant H2A.z
at promoters of neuronal activity-dependent genes in vivo, thereby triggering their shutoff. Purification of
ribosome-associated mRNAs from synchronously developing granule neurons shows that conditional knockout
of Chd4 impairs shutoff of activity-dependent genes when neurons undergo dendrite pruning in vivo.
Accordingly, Chd4-dependent shutoff of activity genes drives granule neuron dendrite pruning in vivo. Our
findings define an epigenetic mechanism that shuts off activity-dependent transcription and thereby regulates
dendrite patterning in the brain. These findings also raise fundamental questions on the regulation and
mechanisms of Chd4-control of gene expression and neuronal connectivity in the brain. The ATPase Chd4
represents the core subunit of the nucleosome remodeling and deacetylase (NuRD) complex. We will elucidate
the role of the protein Mbd3, which is required for the assembly of the NuRD complex, in Chd4-induced H2A.z-
dependent shutoff of activity genes and granule neuron dendrite patterning in the mouse brain in vivo. We will
also determine whether Chd4, like the chromatin remodeling enzyme p400, directly incorporates H2A.z into
nucleosomes, and assess the role of p400 in the Chd4/H2A.z epigenetic pathway. Finally, we will characterize
the biological role of the Chd4/H2A.z epigenetic pathway in granule neuron responses in the context of
cerebellar circuitry. The proposed research will advance our understanding of the epigenetic mechanisms that
control neuronal connectivity in the brain. Because mutations of epigenetic regulators including Chd4 cause
neurodevelopmental disorders of cognition including autism and intellectual disability, our studies will also shed
light on pathogenic mechanism underlying these major disorders of the brain.

## Key facts

- **NIH application ID:** 10359207
- **Project number:** 5R01NS041021-20
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Harrison W Gabel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $577,776
- **Award type:** 5
- **Project period:** 2001-07-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10359207

## Citation

> US National Institutes of Health, RePORTER application 10359207, SIGNAL TRANSDUCTION PATHWAYS REGULATING NEURON DIFFERENTIATION (5R01NS041021-20). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10359207. Licensed CC0.

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