Control of Neuronal Differentiation in the Cerebellum

小脑神经元分化的控制

• 批准号: 6687155
• 负责人: ANNA A PENN
• 金额: $ 17.24万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6687155
• 关键词: cell differentiation; cerebellum; developmental genetics; developmental neurobiology; genetically modified animals; granule cell; laboratory mouse; microarray technology; neurogenesis; neurogenetics; stem cells

DESCRIPTION (provided by applicant): The cerebellum is one of the earliest brain regions to develop, but it is mature many months after birth. This long developmental period makes it susceptible to pre- and post-natal disruptions. It also makes it highly amenable to study; its anatomical development is well described. However, genetic control of transitions from cerebellar stem cells to mature neurons remains largely unknown. The control granule cell generation, the most numerous CNS neurons, will be examined. The cerebellum arises from two germinal zones: The rhombic lip, giving rise to granule cells, and the ventricular zone, giving rise to all other cells. Cells proliferate at the rhombic lip, migrate to the external germinal layer (EGL), proliferate as granule cell precursors (GCPs) and migrate past the Purkinje neurons as they become mature granule cells. We hypothesize that key regulatory signals underlying the shift from proliferation to differentiation can be identified by comparing the genetic changes occurring at the rhombic lip and the EGL. We know that Sonic hedgehog (Shh) is a potent mitogen for GCPs, which express the Shh receptor, Patched1 (Ptcl). Reduced ptcl function may give rise to abnormal proliferation of GCPs, causing meduloblastoma. Using Shh we have already identified gene expression changes that occur as GCPs go from being non-proliferating to proliferating. A role for Shh and Ptcl earlier, at the rhombic lip, has not yet been explored. The transition from self-renewing precursor to differentiating granule cell will be analyzed by: 1) Characterizing the phenotypic potential of cells isolated from the cerebellar primordium and rhombic lip, 2) elucidating the genetic program controlling the transition points between these stages, and 3) testing genes identified as potential regulators to determine how progenitor cells cease proliferation and start to differentiate. Ultimately, to control neuronal precursor cells in a therapeutic, directed manner in any region, from cerebellum to cortex, we must understand the mechanisms underlying the shift from proliferation to differentiation. My goal is to develop molecular biology skills to complement my previous physiology and anatomy training. As a neonatologist, I will bring these tools to bear on critical issues in neurodevelopment.

描述（由申请人提供）：小脑是最早发育的大脑区域之一，但它在出生后几个月就成熟了。漫长的发育期使其容易受到产前和产后的干扰。这也使得它非常适合学习；它的解剖学发育有很好的描述。然而，小脑干细胞向成熟神经元转变的遗传控制仍然很大程度上未知。将检查控制颗粒细胞的产生，即数量最多的中枢神经系统神经元。小脑起源于两个生发区：菱形唇，产生颗粒细胞，以及脑室区，产生所有其他细胞。细胞在菱形唇处增殖，迁移到外生发层 (EGL)，作为颗粒细胞前体 (GCP) 增殖，并在成为成熟颗粒细胞时迁移经过浦肯野神经元。我们假设通过比较菱形唇和 EGL 发生的遗传变化可以识别从增殖到分化转变的关键调控信号。我们知道 Sonic hidehog (Shh) 是 GCP 的有效有丝分裂原，GCP 表达 Shh 受体 Patched1 (Ptcl)。 ptcl功能降低可能导致GCP异常增殖，导致髓母细胞瘤。使用Shh，我们已经确定了当GCP从不增殖到增殖时发生的基因表达变化。此前，Shh 和 Ptcl 在菱形唇部的作用尚未被探索。将通过以下方式分析从自我更新前体细胞到分化颗粒细胞的转变：1）表征从小脑原基和菱形唇分离的细胞的表型潜力，2）阐明控制这些阶段之间过渡点的遗传程序，以及3）测试被确定为潜在调节因子的基因，以确定祖细胞如何停止增殖并开始分化。最终，为了以治疗性、定向的方式控制从小脑到皮质任何区域的神经元前体细胞，我们必须了解从增殖到分化转变的机制。我的目标是发展分子生物学技能，以补充我之前的生理学和解剖学培训。作为一名新生儿科医生，我将利用这些工具来解决神经发育的关键问题。