Mechanisms regulating neural progenitor expansion in the developing brain
调节大脑发育中神经祖细胞扩张的机制
基本信息
- 批准号:9151528
- 负责人:
- 金额:$ 32.81万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-09-01 至 2021-08-31
- 项目状态:已结题
- 来源:
- 关键词:AblationAllelesBindingBiogenesisBiological AssayBody SizeBrainCell CycleCell Cycle ProgressionCell DeathCellsCentriolesChromosomesCiliaDataDefectDiseaseEmbryoExhibitsFibroblastsFundingGeneticGenetic studyGoalsGrantHumanHuman GeneticsIndividualIntellectual functioning disabilityLeadLengthLinkMicrocephalyMitosisMitoticModelingMusMutant Strains MiceMutationNonsense MutationOnline Mendelian Inheritance In ManOrganPatientsPhenocopyPlayPopulationPositioning AttributeProteinsRegulationRoleSpecificityStaining methodStainsTestingalpha Tubulinbrain sizecilium biogenesiscongenital brain disorderimprovedinsightkinetosomeknock-downmouse modelmutantnerve stem cellnovel
项目摘要
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.
项目总结
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Jianfu Chen其他文献
Jianfu Chen的其他文献
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{{ truncateString('Jianfu Chen', 18)}}的其他基金
Selective neurovascular regulation by a vascular dementia-related noncoding RNA Snord118
血管性痴呆相关非编码 RNA Snord118 的选择性神经血管调节
- 批准号:
10435866 - 财政年份:2022
- 资助金额:
$ 32.81万 - 项目类别:
Neurovascular functions of a small RNA Snord118-mediated ribosome biogenesis
小RNA Snord118 介导的核糖体生物发生的神经血管功能
- 批准号:
10355240 - 财政年份:2022
- 资助金额:
$ 32.81万 - 项目类别:
Mechanisms regulating neural progenitor expansion in the developing brain
调节大脑发育中神经祖细胞扩张的机制
- 批准号:
9557551 - 财政年份:2016
- 资助金额:
$ 32.81万 - 项目类别:
Mechanisms regulating neural progenitor expansion in the developing brain
调节大脑发育中神经祖细胞扩张的机制
- 批准号:
10009484 - 财政年份:2016
- 资助金额:
$ 32.81万 - 项目类别:
Genetic analysis of a microRNA pathway regulating neural tube closure
调节神经管闭合的 microRNA 通路的遗传分析
- 批准号:
9564399 - 财政年份:2016
- 资助金额:
$ 32.81万 - 项目类别:
Genetic analysis of a microRNA pathway regulating neural tube closure
调节神经管闭合的 microRNA 通路的遗传分析
- 批准号:
9248454 - 财政年份:2016
- 资助金额:
$ 32.81万 - 项目类别:
Mechanisms regulating neural progenitor expansion in the developing brain
调节大脑发育中神经祖细胞扩张的机制
- 批准号:
9316724 - 财政年份:2016
- 资助金额:
$ 32.81万 - 项目类别:
Genetic analysis of a microRNA pathway regulating neural tube closure
调节神经管闭合的 microRNA 通路的遗传分析
- 批准号:
9075831 - 财政年份:2016
- 资助金额:
$ 32.81万 - 项目类别:
Mechanisms regulating neural progenitor expansion in the developing brain
调节大脑发育中神经祖细胞扩张的机制
- 批准号:
9768241 - 财政年份:2016
- 资助金额:
$ 32.81万 - 项目类别:
Wdr62 in neural development and malformations of cortical development disease
Wdr62 在神经发育和皮质发育畸形疾病中的作用
- 批准号:
8795739 - 财政年份:2012
- 资助金额:
$ 32.81万 - 项目类别:
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