Developmental control of cell cycle exit

发展的一个未解之谜涉及如何控制增长和形态。细胞的调节 增殖是这个问题的核心，而控制细胞周期停滞的机制是细胞 差异化是特别相关的。细胞周期退出在癌变过程中也是至关重要的，在癌症发生过程中它被绕过。 在伤口愈合和再生方面，它被逆转以允许新的增殖。而细胞周期 Exit已经在细胞培养和体内几种模式生物中进行了研究，这些机制相互耦合 细胞周期调控装置的分化信号仍然知之甚少。没有通用的范式 存在对细胞分化与G1期停滞的普遍耦合的解释。这项建议是为了研究细胞 果蝇在分化时的周期存在于三个特征很好的环境中：胚胎、翅膀和 眼睛。我们将验证分化信号主要抑制细胞周期转录的假设 通过E2F/Rb非依赖机制控制基因。在目标1中，我们操纵已知细胞的活动 周期控制基因来定义触发细胞周期退出的机制，我们还分析了 退出过程中的基因表达。在目标2中，我们研究了转录调控区域 关键的细胞周期控制基因，细胞周期蛋白E，识别顺式作用元件，并最终识别反式作用因子， 在分化过程中调节其沉默。在目标3中，我们对果蝇进行遗传筛选，以确定新的基因 在功能上对细胞周期退出非常重要。合并后的结果应该区分出许多 文献中提出的细胞周期退出的合理解释，确定了新的基因产物 细胞周期退出，并为未来研究分化信号如何与 该细胞周期控制装置。因为协调组织模式的遗传网络，细胞 果蝇和人类之间的分化和细胞周期控制是保守的，这里得到的结果 应该为正在进行的人类发展和疾病研究提供信息。

An unsolved mystery of development concerns how growth and form are controlled. The regulation of cell Droliferation is central to this problem, and the mechanisms controlling cell cycle arrest upon cell differentiation are particularly relevant. Cell cycle exit is also critical in carcinogenesis, where it is bypassed, and in wound healing and regeneration, where it is reversed to allow renewed proliferation. While cell cycle exit has been studied in cell culture and in vivo in several model organisms, the mechanisms that couple differentiation signals to the cell cycle control apparatus remain poorly understood. No general paradigm exists explaining the ubiquitous coupling of cell differentiation to G1 arrest. This proposal is to study cell cycle exit at differentiation in Drosophila in three well-characterized contexts: the embryo, the wing, and the eye. We will test the hypothesis that differentiation signals dominantly suppress the transcription of cell cycle control genes via an E2F/RB-independent mechanism. In Aim 1, we manipulate the activity of known cell cycle control genes to define the mechanism that triggers cell cycle exit, and we also analyze changes in gene expression during the exit process. In Aim 2, we study the transcriptional regulatory region of the critical cell cycle control gene, cyclin E, to identify cis-acting elements, and eventually tran-acting factors, that mediate its silencing at differentiation. In Aim 3 we perform genetic screens in the fly to identify novel genes that are functionally important for cell cycle exit. The combined results should distinguish between the many plausible explanations of cell cycle exit suggested in the literature, identify new gene products that mediate cell cycle exit, and provide a working paradigm for future studies of how differentiation signals interface with the cell cycle control apparatus. Because the genetic networks that orchestrate tissue patterning, cell differentiation, and cell cycle control are conserved between Drosophila and man, the results obtained herein should inform ongoing studies of human development and disease.