# Discovering miRNA-Mediated Mechanisms of Interneuron Development

> **NIH NIH F31** · SCRIPPS RESEARCH INSTITUTE, THE · 2022 · $41,165

## Abstract

Project Summary
 Inhibitory interneuron (IN) development requires successful completion of a series of
processes, which include long-range migration, lamination, molecular specification, circuit
integration, and functional maturation. IN dysfunction is highly implicated in neurodevelopmental
and psychiatric disorders, so understanding how INs achieve their mature distribution, number,
and identity is critical to understanding disease. Cell-intrinsic gene expression programs, involving
the precise regulation of huge sets of genes, interact with environmental cues to control
development. MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression known
to be necessary for multiple aspects of IN development, yet the specific mechanisms by which
miRNAs do this remain unknown, in part because IN-specific patterns of miRNA activity were
unknown. We bridged this gap by performing Ago cross-linking and immunoprecipitation followed
by sequencing (Ago CLIPseq) to comprehensively profile the IN targetome at developmental
timepoints. However, identifying developmental pathways regulated by individual miRNAs has
been challenging because the targetome is extremely complex—miRNAs simultaneously regulate
many genes and can compensate for each other through co-targeting relationships. We propose
an alternative approach of investigating miRNA regulation on a gene-by-gene level. Through
bioinformatic analysis of the CLIPseq data, I identified miRNA hotspots, or genes co-targeted by
multiple miRNAs, which we hypothesize is a signature of strong miRNA regulation shared by
many key developmental genes. With these candidate genes, I am now poised to untangle how
miRNA regulation of specific genes controls particular aspects of IN development. I will use new
CRISPR-based methods for disrupting miRNA regulation of candidate genes in a cell type-specific
manner and screen for developmental defects, first using a set of in vitro and in vivo readouts for
IN migration, survival, and subtype specification. Then, I will assess perturbations of overall
developmental trajectory using targeted Perturb-seq, which harnesses the transcriptome as a
complex readout of maturation state in single cells. Ultimately, with this experimental pipeline I
will discover genes and miRNA mechanisms that control IN development.

## Key facts

- **NIH application ID:** 10477017
- **Project number:** 5F31NS118982-02
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Jessica Xinyun Du
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $41,165
- **Award type:** 5
- **Project period:** 2021-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10477017

## Citation

> US National Institutes of Health, RePORTER application 10477017, Discovering miRNA-Mediated Mechanisms of Interneuron Development (5F31NS118982-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10477017. Licensed CC0.

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