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）：神经祖细胞的增殖、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，包括神经营养素家族。这些过程已被广泛研究。小脑颗粒细胞祖细胞 (GCP) 是大脑中最丰富的细胞类型，其大部分发育是在出生后的外部颗粒层 (EGL) 中增殖的，这是一个过渡层。这些细胞在 EGL 的外部增殖，而在 EGL 的内部，细胞退出细胞周期并开始向小脑内部迁移。在小脑发育过程中，p75 神经营养素受体 (p75NTR) 在 EGL 中高度表达，一旦细胞开始迁移，其功能就会消失。我们的初步数据表明，这种发育中的神经元群体中的 p75NTR 会促进细胞周期退出并抑制迁移，而缺乏这种受体的小鼠表现出增殖标记物增加、细胞周期退出延迟和小脑增大。提出 p75NTR 在调节颗粒细胞祖细胞从增殖群体向迁移群体转变的时间中起着至关重要的作用 p75NTR-/- 小鼠在成年时具有结构缺陷。我们的初步数据表明，EGL 中缺乏 p75NTR 的成年小鼠在发育过程中表现出运动行为缺陷，这表明这些发育事件的调节对成年小鼠具有长期持续的影响，因此，我们期望在成年小鼠中定义 p75NTR 的新作用。发育中的大脑对小脑结构和功能有长期影响。