# Non-coding RNA regulation of early neural development

> **NIH NIH R01** · UNIVERSITY OF COLORADO · 2022 · $551,783

## Abstract

Defects in neuroepithelial progenitor self-renewal and differentiation can result in profound neurodevelopmental
disorders including devastating birth defects such as microcephaly. The long-term objective of the proposed
studies is to understand how neuroepithelial progenitor cell self-renewal and differentiation are coordinated. This
proposal specifically focuses on a long non-coding RNA (lncRNA) that is expressed early in mouse
neuroepithelial progenitor cells and, as differentiation proceeds, the lncRNA transcript is processed to yield a
microRNA that is involved in neuronal differentiation. Moreover, the lncRNA physically interacts with key
microcephaly proteins but the functional relationship between the lncRNA and these proteins is unknown. The
major questions addressed in three Aims are as follows. Aim 1 will test the hypothesis that the lncRNA functions
- independent of the miRNA - in regulating neuroepithelial progenitor proliferation and survival. Aim 1 creates
cell lines and mouse models with specific deletion mutations, including a small deletion of this locus observed in
a patient with microcephaly, for functional studies. Aim 2 will explore the cellular mechanism underlying the
microcephaly phenotype, preliminary data which suggests a mitotic arrest. Moreover, Aim 2 will address the
hypothesis that the lncRNA functions as a scaffold to help maintain sister chromatid cohesion through its
interactions with the Cohesin complex, which is also implicated in microcephaly. Aim 3 will explore the
mechanism underlying the temporal-spatial difference between the lncRNA host transcript and the embedded
miRNA. Our overall goal is to discover new mechanisms that coordinate neuroepithelial progenitor cell
proliferation and differentiation, as well as to decipher how this unexplored lncRNA mechanistically acts to allow
normal brain growth. Harnessing the potential of neuroepithelial progenitor cells holds promise for the treatment
of neuronal injury and neurodegenerative diseases, and dysfunction of neuroepithelial progenitors is at the root
of numerous neurological disorders. Our studies will provide mechanistic links between a novel lncRNA and
known microcephaly proteins to greatly extend our knowledge of this profound brain disorder.

## Key facts

- **NIH application ID:** 10318617
- **Project number:** 5R01NS110887-03
- **Recipient organization:** UNIVERSITY OF COLORADO
- **Principal Investigator:** Lee A. Niswander
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $551,783
- **Award type:** 5
- **Project period:** 2019-12-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10318617

## Citation

> US National Institutes of Health, RePORTER application 10318617, Non-coding RNA regulation of early neural development (5R01NS110887-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10318617. Licensed CC0.

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