Regulation of Cerebellum Growth and Development

描述(申请人提供)：小脑正常发育 需要有丝分裂信号和反馈机制来限制细胞分裂 合适的时间和地点。我们将研究控制正常的机制 小脑生长，并在小脑肿瘤发生过程中失效。两个增长 有助于小脑发育的脑区：浦肯野所在的脑室区 和其他细胞形成，而外部生发层产生 颗粒细胞，大脑中最丰富的神经元类型。我们已经展示了 由浦肯野细胞产生的Sonic hedgehog(Shh)信号蛋白是一种 强大的小脑颗粒细胞前体细胞有丝分裂原。打补丁的1 由颗粒细胞前体产生的跨膜蛋白是一种受体 嘘。Shh通过阻止Patched1激活靶基因的转录 抑制它们的转录。我们已经证明，减少的人体补丁1 功能与散发性和遗传性髓母细胞瘤有关。 髓母细胞瘤是儿童恶性脑肿瘤中最常见的类型， 它的死亡率约为50%。我们已经制作了一个小鼠模型 基于人类遗传疾病的髓母细胞瘤，减少 补丁1功能导致肿瘤频发。肿瘤细胞被标记为 LacZ的表达，因此它们可以在明显的肿瘤形成之前很久就被识别出来。 这使得对肿瘤发生的早期阶段的研究成为可能。我们建议 Shh信号如何控制正常颗粒细胞发育的实验 通过影响细胞周期和其他调节因子，以及如何减少补丁1 功能障碍会导致髓母细胞瘤。具体目标是：1.调查Shh 小脑颗粒对细胞周期和细胞分化的调控 细胞前体。2.研究颗粒细胞前体细胞如何停止反应 Shh的促有丝分裂作用并开始分化和迁移。3.使用 建立小鼠髓母细胞瘤模型，探讨肿瘤发生机制。

DESCRIPTION (provided by applicant): The normal growth of the cerebellum requires mitogenic signals and feedback mechanisms that limit cell division to the proper times and places. We will investigate mechanisms that control normal cerebellum growth and that fail during cerebellar tumorigenesis. Two growth zones contribute to cerebellar development: the ventricular zone where Purkinje and other cells form, and the external germinal layer that gives rise to granule cells, the most abundant type of neuron in the brain. We have shown that Sonic hedgehog (Shh) signaling protein, produced by Purkinje cells, is a powerful mitogen for cerebellar granule cell precursors. The Patched 1 transmembrane protein, produced in granule cell precursors, is a receptor for Shh. Shh activates the transcription of target genes by preventing Patched1 from inhibiting their transcription. We have shown that reduced human PATCHED1 function is associated with sporadic and inherited types of medulloblastoma. Medulloblastoma is the most common type of childhood malignant brain tumor, and it has an approximately 50 percent mortality rate. We have made a mouse model of medulloblastoma based on the human genetics of the disease, with reduced patched1 function leading to frequent tumors. The tumor cells are marked by lacZ expression, so they can be recognized long before an overt tumor forms. This allows investigation of early stages of tumorigenesis. We propose experiments to learn how Shh signaling controls normal granule cell development by affecting cell cycle and other regulators, and how reduced Patched 1 function leads to medulloblastoma. The specific aims are: 1. To investigate Shh regulation of the cell cycle and cell differentiation in cerebellar granule cell precursors. 2. To investigate how granule cell precursors stop responding to mitogenic effects of Shh and begin differentiation and migration. 3. To use mouse models of medulloblastoma to investigate mechanisms of tumorigenesis.