# The Role of QKI in Human Neuron-Glia Lineage Development

> **NIH NIH F31** · EMORY UNIVERSITY · 2020 · $45,520

## Abstract

PROJECT SUMMARY
The human brain is composed of neurons and glia, both of which are derived from multipotent neural
progenitor cells (NPCs). Precisely controlled differentiation of multipotent NPCs into neuronal and glial
lineages is critical for normal brain development and function, as well as repair of lesions in the central
nervous system. Abnormalities arising during this process are thought to underlie the pathogenesis of
many neurobiological diseases and neuropsychiatric disorders. Malfunction of the selective RNA binding
protein Quaking (QKI) is one such abnormality implicated in neuropsychiatric diseases and myelin
disorders in which aberrant neuron-glia development contributes to disease etiology. In neural lineage,
QKI expression is detected in rodent NPCs and continues to increase in glia, but is absent in mature
neurons. Emerging evidence suggests that silencing of QKI during mouse brain development advances
neuronal differentiation. However, whether and how QKI indeed controls human neuron-glia fate selection
still remains undefined. Three QKI isoforms with distinct nuclear-cytoplasmic distribution are derived from
alternative splicing of C-terminal coding exons. Our preliminary data revealed that cyclin-dependent kinase
5 (CDK5) phosphorylates QKI, which drastically enhances nuclear translocation of cytoplasmic QKI
isoforms. Moreover, in a human NPC cell line, CDK5-dependent phosphorylation of QKI regulates the
biogenesis of microRNA-124 (miR-124), a key factor that drives neuronal differentiation and inhibits glial
lineage in rodents. These data lead to our intriguing hypothesis that the CDK5QKI-miR-124 pathway in
human NPCs (hNPCs) may control neuron-glia fate decision and lineage differentiation. In this application,
we propose two specific aims to test the aforementioned hypothesis. Aim 1: We will delineate molecular
mechanisms by which QKI regulates miR-124 biogenesis in hNPCs. Aim 2: Using CRISPR-Cas9
technology, we will delete the 3’ exons that encode individual QKI isoforms in hNPCs and determine the
roles of each QKI isoform in hNPC renewal and neuron-glia fate selection. These studies will uncover
novel mechanisms that control microRNA-driven neuron-glia lineage development and provide the first
evidence demonstrating the function of individual QKI isoforms in hNPCs.

## Key facts

- **NIH application ID:** 9992561
- **Project number:** 1F31NS113572-01A1
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Izabela Suster
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 1
- **Project period:** 2020-04-08 → 2023-04-07

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9992561

## Citation

> US National Institutes of Health, RePORTER application 9992561, The Role of QKI in Human Neuron-Glia Lineage Development (1F31NS113572-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9992561. Licensed CC0.

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