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Role of the p75 neurotrophin receptor in the developing cerebellum

p75 神经营养素受体在小脑发育中的作用

基本信息

批准号：
9177042
负责人：
WILMA J FRIEDMAN
金额：
$ 38.75万
依托单位：
RUTGERS THE STATE UNIV OF NJ NEWARK
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-12-15 至 2018-12-14
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9177042
关键词：
Adult Apoptosis Apoptotic Attenuated Behavior Brain Brain-Derived Neurotrophic Factor Bromodeoxyuridine Cell Cycle Cell Proliferation Cells Cerebellum Cognitive Cytoplasmic Granules Data Development Developmental Delay Disorders Event Family Goals HDAC1 gene Health Impaired cognition In Vitro Knockout Mice Label Lead Ligands Long-Term Effects Mediating Mitogens Monitor Motor Mus NGFR Protein Neurons Neurotrophic Tyrosine Kinase Receptor Type 2 Outcome Play Population Process Proliferating Proliferation Marker Regulation Role SHH gene Signal Transduction Stem cells Structure Testing Time Withdrawal cell motility cell type granule cell in vivo insight migration motor disorder nerve stem cell nervous system development neuron development neurotrophic factor novel postnatal prevent progenitor receptor receptor expression transcription factor

项目摘要

DESCRIPTION (provided by applicant): Regulation of proliferation, differentiation, and migration of neural progenitor cells is critical for the normal development of the nervous system. Many factors can influence these events, including the neurotrophin family of factors. These processes have been extensively studied in cerebellar granule cell progenitors (GCP), the most abundant cell type in the brain, which undergo much of their development postnatally. GCPs proliferate in external granule layer (EGL), a transient layer of the cerebellum, and migrate internally to form the internal granule layer (IGL). In the external part of the EGL these cells proliferate, while in the internal part of the EGL the cells exit the cell cycle and start to migrae toward the inside of the developing cerebellum. The p75 neurotrophin receptor (p75NTR) is highly expressed in the EGL during development of the cerebellum, and is absent once the cells begin to migrate. The function of p75NTR in this developing neuronal population has not been defined. Our preliminary data demonstrate that this receptor promotes withdrawal from the cell cycle and inhibits migration, and mice lacking this receptor show increased markers of proliferation, delayed cell cycle exit, and an enlarged cerebellum. We propose that p75NTR plays a crucial role in regulating the timing of the transition of granule cell progenitors from a proliferating to a migrating population. The p75NTR-/- mice have structural deficits in the adult cerebellum, and our preliminary data indicate that adult mice lacking p75NTR in the EGL during development show deficits in motor behavior, suggesting that modulation of these developmental events have long-lasting consequences in the adult. Thus, we expect to define novel roles for p75NTR in the developing brain that have long-term consequences for cerebellar structure and function.

描述（由申请人提供）：神经祖细胞增殖、分化和迁移的调节对于神经系统的正常发育至关重要。许多因素可以影响这些事件，包括神经营养因子家族。这些过程已经在小脑颗粒细胞祖细胞（GCP）中得到了广泛的研究，GCP是大脑中最丰富的细胞类型，其大部分发育都是在出生后进行的。GCPs在小脑的过渡层外颗粒层（EGL）中增殖，并向内部迁移形成内颗粒层（IGL）。在EGL的外部，这些细胞增殖，而在EGL的内部，细胞退出细胞周期并开始向发育中的小脑内部迁移。p75神经营养因子受体（p75 NTR）在小脑发育期间在EGL中高度表达，并且一旦细胞开始迁移就不存在。p75 NTR在这一发育中的神经元群体中的功能尚未确定。我们的初步数据表明，这种受体促进退出细胞周期，抑制迁移，缺乏这种受体的小鼠表现出增加的增殖标志物，延迟细胞周期退出和小脑扩大。我们建议，p75 NTR在调节颗粒祖细胞从增殖到迁移的群体的过渡的时间中起着至关重要的作用。p75 NTR-/-小鼠在成年小脑中存在结构缺陷，我们的初步数据表明，在发育过程中EGL中缺乏p75 NTR的成年小鼠表现出运动行为缺陷，这表明这些发育事件的调节在成年中具有长期的后果。因此，我们希望确定新的作用，p75 NTR在大脑发育中有长期的后果小脑的结构和功能。