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The mechanism of Notch signaling pathway in radial glial development

Notch信号通路在放射状胶质细胞发育中的作用机制

基本信息

批准号：
7679113
负责人：
YOICHI KATO
金额：
$ 7.35万
依托单位：
FLORIDA STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-01 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7679113
关键词：
Address Adult Astrocytes Brain Brain Neoplasms Cell Therapy Cells Characteristics Chronic Lymphocytic Leukemia Co-Immunoprecipitations Cortical Dysplasia Development Disease Embryo Embryonic Development Ependymal Cell Ependymoma Epilepsy Future Maintenance Malignant Neoplasms Mammals Mass Spectrum Analysis Mediating Mental Retardation Molecular Nature Nervous system structure Neuraxis Neuroglia Neurons Notch Signaling Pathway Oligodendroglia POZ-zinc Pathology Pathway interactions Radial Reporting Research Personnel Role Schwann Cells Signal Transduction Staging Stem cells Stroke Structure of germinal center of lymph node Testing Xenopus Xenopus laevis Zinc Fingers base cell type glial cell development leukemia/lymphoma migration myelination nerve stem cell neurogenesis notch protein novel oligodendrocyte precursor precursor cell programs scaffold segregation transcription factor

项目摘要

DESCRIPTION (provided by applicant): The Notch signaling pathway is evolutionarily conserved. In the developing nervous system, Notch signaling is required at multiple stages to govern cell fate decisions, from the first segregation of neural precursors, to the terminal specification of cells including neurons and glia. Notch signaling strongly inhibits neurogenesis and triggers the differentiation of some types of glia including Schwann cells, M¿ller cells, astrocytes, Bergmann glia, and radial glia. Furthermore, Notch signaling contributes to the maintenance of oligodendrocyte precursor cells as well as oligodendrocyte maturation and myelination. Radial glial cells are one of macroglial cell types and function as scaffolding cells for neuronal migration and neural progenitor cells. Importantly, previous study shows defective radial glia function in the developing brain is causative for cortical dysplasia, and the concomitant pathologies of epilepsy and mental retardation. Radial glial cells are also implicated as candidate stem cells of ependymoma, a brain tumor. Despite their functional importance, the molecular mechanism that underlies radial glial development has been poorly understood. In their studies examining the role of Notch signaling in radial glial formation in Xenopus laevis, the investigators have uncovered that Suppressor of Hairless [Su(H)], a transcription factor required for Notch signaling, is sufficient but not required for radial glial formation. Similar findings have been hinted at in mammalian studies, and this strongly suggests the existence of novel Su(H)-independent Notch pathway that is employed for radial glial development. To elucidate the molecular mechanism of Su(H)-independent pathway in radial glial formation, the investigators have identified B-cell leukemia/lymphoma 6 (BCL6) as a Notch-associated factor by coimmunoprecipitation with mass spectrometry analysis. BCL6 is a BTB/POZ-zinc-finger transcriptional factor and has been reported to be required for normal germinal center (GC) development. While BCL6 is expressed in the developing mammalian central nervous system, the role of BCL6 during embryogenesis still remains unclear. To test whether BCL6 is involved in Su(H)-independent Notch signaling pathway during radial glial development, the investigators propose to characterize the role of BCL6 in Su(H)-independent Notch signaling pathway during Xenopus radial glial formation in Specific Aim 1, and investigate the role of BCL6 in mammalian radial glial formation in Specific Aim 2.

描述（由申请人提供）：Notch信号通路在进化上是保守的。在发育中的神经系统中，Notch信号传导在多个阶段都是必需的，以控制细胞的命运决定，从神经前体的第一次分离到包括神经元和神经胶质在内的细胞的终末特化。 Notch信号强烈抑制神经发生并触发某些类型神经胶质细胞的分化，包括施万细胞、穆勒细胞、星形胶质细胞、伯格曼神经胶质细胞和放射状神经胶质细胞。此外，Notch信号传导有助于少突胶质细胞前体细胞的维持以及少突胶质细胞成熟和髓鞘形成。放射状胶质细胞是大胶质细胞的一种，是神经元迁移和神经前体细胞的支架细胞。重要的是，先前的研究表明，发育中的大脑中放射状胶质细胞功能缺陷是皮质发育不良以及伴随的癫痫和智力低下的病理学的原因。放射状胶质细胞也被认为是室管膜瘤（一种脑肿瘤）的候选干细胞。尽管其功能的重要性，放射状胶质细胞的发展的分子机制，一直知之甚少。在他们研究Notch信号在非洲爪蟾放射状神经胶质形成中的作用的研究中，研究人员发现，Notch信号所需的转录因子无毛抑制因子[Su（H）]是放射状神经胶质形成所必需的，但不是必需的。在哺乳动物研究中也有类似的发现，这有力地表明存在新的Su（H）-非依赖性Notch途径，其用于放射状神经胶质细胞的发育。为了阐明Su（H）非依赖性通路在放射状胶质细胞形成中的分子机制，研究人员通过免疫共沉淀和质谱分析将B细胞白血病/淋巴瘤6（BCL 6）鉴定为Notch相关因子。 BCL 6是一种BTB/POZ锌指转录因子，据报道是正常生发中心（GC）发育所必需的。虽然BCL 6在发育中的哺乳动物中枢神经系统中表达，但BCL 6在胚胎发生过程中的作用仍不清楚。为了测试BCL 6是否参与放射状胶质细胞发育过程中的Su（H）-非依赖性Notch信号通路，研究人员提出在Specific Aim 1中表征BCL 6在非洲爪蟾放射状胶质细胞形成过程中的Su（H）-非依赖性Notch信号通路中的作用，并在Specific Aim 2中研究BCL 6在哺乳动物放射状胶质细胞形成中的作用。