Role of the p75 neurotrophin receptor in the developing cerebellum

 描述(由申请人提供)：调节神经前体细胞的增殖、分化和迁移对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的因素。这些过程在小脑颗粒细胞前体细胞(GCP)中得到了广泛的研究，GCP是大脑中最丰富的细胞类型，它们在出生后经历了大部分的发育。GCP在小脑的暂时性外颗粒层(EGL)中增殖，在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，开始向发育中的小脑内部偏头痛。P75神经营养因子受体(P75NTR)在小脑发育过程中高表达于EGL，一旦细胞开始迁移就不表达。P75NTR在这个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，这种受体促进了细胞周期的退出并抑制了迁移，而缺乏这种受体的小鼠表现出增殖标志的增加，细胞周期退出的延迟，以及小脑的增大。我们认为p75NTR在调节颗粒细胞前体细胞从增殖群体向迁移群体转变的时间上起着至关重要的作用。P75NTR-/-小鼠在成年小脑中存在结构性缺陷，我们的初步数据表明，在发育过程中EGL中缺乏p75NTR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人中具有长期的后果。因此，我们希望定义p75NTR在发育中的大脑中对小脑结构和功能具有长期影响的新角色。

 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.