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）：小脑是最早开发的大脑区域之一，但出生后的许多月就成熟。这个漫长的发育时期使其容易受到产前和产后中断的影响。这也使其高度适合学习；它的解剖学发展得到了很好的描述。然而，从小脑干细胞到成熟神经元的转变的遗传控制仍然在很大程度上未知。将检查控制颗粒细胞的产生，最多的CNS神经元。小脑源自两个生发区域：菱形唇，产生颗粒细胞和心室区，从而产生所有其他细胞。细胞在菱形唇部增殖，迁移到外部生发层（EGL），作为颗粒细胞前体（GCP）增殖，并在它们成为成熟的颗粒细胞时迁移过普kinje神经元。我们假设可以通过比较龙骨唇和EGL的遗传变化来确定从增殖到分化转移的关键调节信号。我们知道Sonic刺猬（SHH）是GCP的有效有丝分裂原，表达SHH受体Patched1（PTCL）。 PTCL功能降低可能导致GCP的异常增殖，从而导致核母细胞瘤。使用SHH，我们已经确定了GCP从非增殖到增殖时发生的基因表达变化。尚未探索SHH和PTCL的角色，尚未探索菱形唇部。 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.最终，要以从小脑到皮质的任何区域的治疗性，定向方式来控制神经元前体细胞，我们必须了解从增殖到分化转移的转移的机制。我的目标是发展分子生物学技能，以补充我以前的生理学和解剖学培训。作为一名新生儿学家，我将把这些工具带到神经发育中的关键问题上。