# Non-cell autonomous mechanisms of neural circuit wiring mediated by chromatin regulation

> **NIH NIH F31** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $37,476

## Abstract

Abstract
The cerebral cortex is the mammalian brain center for remarkable cognitive, perceptive, and motor capabilities,
the execution of which depends on precise establishment of neuronal connectivity during development. Miswiring
of cortical circuitry can contribute to developmental brain disorders. The formation of cortical circuits depends on
both cell and non-cell autonomous mechanisms that underlie axon growth and pathfinding. These mechanisms
are under precise transcriptional regulation that enables timely, coordinated expression of guidance cues and
receptors to spatiotemporally control circuit wiring. Emerging studies have highlighted the roles of chromatin in
transcriptional control, and defects in chromatin remodeling complexes are linked genetic disorders of brain
developmental. The mechanisms by which altered chromatin regulation contributes to normal and disordered
circuit development, however, remain incompletely understood. Coffin-Siris syndrome is a multi-system
developmental disorder characterized by intellectual disability and agenesis of the corpus callosum. Genetic
studies have shown that it is caused by loss-of-function mutations in subunits of the BAF (SWI/SNF-A) chromatin
remodeling complex, a multi-subunit nucleosome remodeling complex that repositions nucleosomes along DNA,
therefore contributing to transcriptional regulation of nearby genes. The BAF complex is well-studied in cancer
and neural crest development. Its role in the developing cerebral cortex, however, is undefined. To gain insights
into the function of the BAF complex in cortical development and circuit wiring, I conditionally deleted Arid1a,
which encodes a key component of the BAF complex, from the developing cortex using Emx1-Cre or Nex-Cre.
The current proposal is supported by my preliminary studies that the BAF complex plays an important role in
cortical neural progenitor cells, but not post-mitotic neurons, for proper development of axon tracts that target
the cortex. Importantly, I uncovered a potential non-cell autonomous role of this complex in the pathfinding of
thalamocortical axons. Here I will test the central hypothesis that the BAF complex non-cell autonomously guides
axon projections targeting the cortex by simultaneously regulating the expression of multiple guidance cues in
neural progenitor cells. This work will: 1) define the cell and non-cell autonomous functions of the BAF complex
in axon pathfinding; and 2) unbiasedly assess transcriptional alterations in the expression of axon guidance cues
in the mutants, using mouse genetics, functional genomics and transcriptomics, and circuit neurobiology
approaches. This work is perfectly in line with my long-term goal to understand the molecular mechanisms
underlying the development and dysfunction of neural circuits in the cerebral cortex. This project will provide me
with essential training in: 1) mouse genetics; 2) functional genomics and transcriptomics; and 3) in vivo gene
manipulation pro...

## Key facts

- **NIH application ID:** 9989649
- **Project number:** 5F31NS110206-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Daniel Doyle
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $37,476
- **Award type:** 5
- **Project period:** 2019-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9989649

## Citation

> US National Institutes of Health, RePORTER application 9989649, Non-cell autonomous mechanisms of neural circuit wiring mediated by chromatin regulation (5F31NS110206-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9989649. Licensed CC0.

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