Control of granule cell poliferation and differentiation

描述（由申请人提供）：虽然取得了进展， 确定调节细胞增殖和分化的因子， 颗粒细胞前体（GCPs），这些因素如何发挥其作用， 细胞周期和分化尚未完全阐明。在这 建议，脑膜信号调节Sonic Hedgehog的可能性 （Shh）诱导的GCP增殖和垂体腺苷酸环化酶激活 将检测肽（PACAP）介导的分化。工作的基础上 提示Myc和CDK 2可能参与Shh诱导的细胞增殖， 这些蛋白质或其辅因子的显性负性形式将用于 研究它们在Shh诱导增殖中的作用。转录因子 已知Gli1、Zic1和Zipro1影响颗粒细胞增殖。 这些转录因子的过表达将与微阵列技术相结合， 分析以鉴定对GCP增殖重要的途径。采取 总之，这些实验将有助于我们理解神经 增殖和分化，并将有助于了解临床 神经管母细胞瘤，一种侵袭性的小儿脑 癌症，这可能是由GCP的增殖失调引起的。

DESCRIPTION (provided by applicant): Although progress has been made in identifying factors that regulate the proliferation and differentiation of granule cell precursors (GCPs), how these factors exert their effects on the cell cycle and differentiation have not been fully elucidated. In this proposal, the possibility that meningeal signals modulate Sonic hedgehog (Shh)-induced GCP proliferation and pituitary adenylate cyclase activating peptide (PACAP)-mediated differentiation will be examined. Building on work that suggests that Myc and CDK 2 may participate in Shh-induced proliferation, dominant negative forms of these proteins or their co-factors will be used to investigate their role in Shh-induced proliferation. The transcription factors Gli1, Zic1, and Zipro1 are known to influence granule cell proliferation. Overexpression of these transcription factors will be coupled with microarray analysis in order to identify pathways important to GCP proliferation. Taken together, these experiments will contribute to our understanding of neural proliferation and differentiation, and will aid in understanding clinical disorders such as medulloblastoma, an aggressive form of pediatric brain cancer, that may arise from the dysregulated proliferation of GCPs.