# Mechanisms regulating neural progenitor expansion in the developing brain

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2020 · $360,938

## Abstract

Project Summary
Recent human genetic studies identified a link between a class of centrosomal proteins and microcephaly, which
is characterized by a selective reduction of brain size in comparison to other organs. The goal of this proposal is
to establish a novel mechanism of microcephaly by understanding how dysregulation of mitotic progression and
cell cycle re-entry leads to neural progenitor cell (NPC) reduction in microcephaly. This contrasts with the
dominant model in the field that disruption of symmetric/asymmetric division of NPCs causes microcephaly.
We will test this mechanism by focusing on WDR62 (MCPH2; OMIM 604317), which is the second most
common genetic cause of human microcephaly and encodes a WD-40 repeat protein.
 We created a hypomorphic mouse model of Wdr62 deficiency and found that mutant mice exhibited
reduced brain sizes due to a decrease in NPCs. Wdr62 deficient NPCs exhibit mitotic progression delay and an
increase in cell death. Wdr62 deficient mouse embryonic fibroblasts (MEFs) showed reduced spindle stability
and spindle assembly checkpoint (SAC) activation. Wdr62 physically and genetically interacts with Aurora A,
an established spindle assembly factor. In addition, Wdr62 localizes to the basal bodies of primary cilia and
regulates cilia disassembly and cell cycle re-entry of MEFs. Depletion of Cep170, another Wdr62 interacting
protein, also results in cilia disassembly, suggesting that Wdr62 may function together with Cep170 to regulate
cilia biogenesis and cell cycle progression. These preliminary data lead to a novel hypothesis that Wdr62
regulates neural progenitor expansion in the developing brain by influencing mitotic progression and cell cycle
re-entry, which are disrupted by disease mutations in a specific manner.
 To test this hypothesis, three specific aims will be pursued: 1) Test the hypothesis that Wdr62 regulates
mitotic progression of neural progenitor cells (NPCs) by influencing spindle integrity; 2) Test the hypothesis
that Wdr62 regulates cilia disassembly and cell cycle re-entry by functioning together with Cep170; 3) Test the
hypothesis that individual disease alleles of WDR62 compromise its specific functions (mitosis or cilia
disassembly) due to loss of regulation of specific Wdr62 interacting proteins. Together, these studies will
improve our understanding of mitosis and cell cycle re-entry regulation of NPCs in the developing brain and
provide novel insights into mechanisms underlying human microcephaly diseases.

## Key facts

- **NIH application ID:** 10009484
- **Project number:** 5R01NS097231-06
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Jianfu Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $360,938
- **Award type:** 5
- **Project period:** 2016-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10009484

## Citation

> US National Institutes of Health, RePORTER application 10009484, Mechanisms regulating neural progenitor expansion in the developing brain (5R01NS097231-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10009484. Licensed CC0.

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