# RNA regulatory networks in neuronal cell type diversity and function

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2022 · $624,986

## Abstract

PROJECT SUMMARY
RNA regulatory networks in neuronal cell type diversity and function
The mammalian brain is probably the most complex organ in the body and its proper function requires
coordination of many diverse types of excitatory and inhibitory neurons that form distinct functional circuitries.
Characterization of neuronal cell types is fundamental to understand not only how the brain works, but also how
specific cell types are selectively affected in multiple neuronal disorders and how this process can be reversed.
A large number of neuronal cell types were recently defined based on their gene expression profiles in bulk and
single cells, and these cell types are organized into a hierarchical cell taxonomy. Alternative splicing is a
mechanism to generate multiple transcript and protein variants with distinct functions, thus providing a major
driving force of the molecular diversity in mammals. The overarching goal of my research group is to understand
the contribution of alternative splicing and the underlying RNA-regulatory networks in the brain and brain-related
disorders. Previous work from multiple groups, including ours, unambiguously demonstrated that the brain has
unique splicing-regulatory programs compared to non-neuronal tissues. Our studies also revealed the
establishment of a pan-neuronal splicing program regulated by multiple RNA-binding proteins (RBPs) during
neural development, and demonstrated the important role of the Rbfox protein family in regulating axonal
maturation and neuronal excitability. However, how alternative splicing contributes to the distinct molecular
profiles of diverse neuronal cell types in the cortex is currently poorly understood. We hypothesize that the
transcriptome diversity generated by highly regulated alternative exons is a major component that specifies
neuronal cell type identity and function. In this application, we describe our preliminary analysis of neuronal cell
type-specific alternative splicing regulation in mouse cortex, which provides strong support for the following
specific aims we would like to pursue: 1) Perform systematic analysis of neuronal cell type-specific alternative
splicing to identify novel neuronal subclasses and regulators using deep sc-RNA-seq data. 2) Validate our
computational predictions and characterize mechanisms of neuronal cell type-specific splicing regulation and
function using two complementary model systems: the distinction of two major subclasses of GABAergic
interneurons originating from caudal (CGE) and medial (MGE) ganglionic eminences, and a GABAergic neuron-
specific microexon in Ank3/Ankyrin G. To achieve our goal, we will use a multidisciplinary approach that
integrates cutting-edge statistical an machine learning methods and multiple in vitro and in vivo experimental
models. This study will generate a global and mechanistic view of precise alternative splicing regulation across
diverse neuronal cell types and illuminate its impact on neuronal structur...

## Key facts

- **NIH application ID:** 10342485
- **Project number:** 1R01NS125018-01
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Chaolin Zhang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $624,986
- **Award type:** 1
- **Project period:** 2021-12-01 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10342485

## Citation

> US National Institutes of Health, RePORTER application 10342485, RNA regulatory networks in neuronal cell type diversity and function (1R01NS125018-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10342485. Licensed CC0.

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