# The Role of NMD in Cortical Neural Progenitor Cells

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA RIVERSIDE · 2024 · $70,137

## Abstract

PROJECT SUMMARY
Mutations in key factors of nonsense-mediated mRNA decay (NMD), including Upf2, Upf3a, Upf3b, and Smg6,
are enriched in various neurodevelopmental diseases. In additional to ensuring transcript quality by degrading
aberrant transcripts with a premature stop codon, NMD modulates stability of selective mRNAs to fine-tune
transcript abundance. Whether and how NMD influences brain development remains elusive. Our long-term
objective is to understand the functional role of NMD regulation for the complicated and dynamic process of
neurogenesis and how its mis-regulation leads to neurodevelopmental disorders. We determine the
requirement of NMD for neural development through selective genetic ablation of Upf2 and in vivo
manipulation of other NMD factors. Our preliminary data show that deletion of UPF2 in neural stem and
progenitors results in microcephaly. UPF2 loss specifically affects the cell cycle and lineage progression of
radial glia cells (RGCs), the major neural progenitor cells in the developing neocortex. We will combine cutting
edge molecular cellular ribogenomics approaches, mouse genetics, and developmental neurobiology to dissect
the mechanisms of NMD regulating neurogenesis. We propose three independent and interrelated aims to
investigate possible variables underlying the microcephaly phenotype. In Aim 1, we will determine the cell
cycle behaviors of RGCs in NMD knockout mice qualitatively and quantitatively and unveil the underlying
regulatory mechanisms. In Aim 2, we will determine the lineage progression of RGCs and the resulting
neuronal outputs per time unit in NMD knockout mice. By characterizing these molecular cellular defects, we
also aim to provide mechanistic insights to transcriptomic regulation of RGC’s lineage transitions. NMD may
regulate cell fates either independent of cell cycle controls or as the consequence of affecting the cell cycle. In
Aim 3, we will test these two hypotheses and leverage our results to reexamine the relationship between cell
cycle and cell fate. Successful completion of these studies will provide fundamental insights into how selective
mRNA stability underlies the highly regulated cortical neurogenesis process in the mammalian brain. The
proposed studies will also shed light on some fundamental questions about the control of cell cycle, cell fate,
and their relationship during neural development.

## Key facts

- **NIH application ID:** 10991767
- **Project number:** 3R01NS125276-03S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA RIVERSIDE
- **Principal Investigator:** Sika Zheng
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $70,137
- **Award type:** 3
- **Project period:** 2021-12-01 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10991767

## Citation

> US National Institutes of Health, RePORTER application 10991767, The Role of NMD in Cortical Neural Progenitor Cells (3R01NS125276-03S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10991767. Licensed CC0.

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