Developmental control of cell cycle exit

发育的一个未解之谜是关于生长和形态是如何被控制的。调节细胞 细胞凋亡是这一问题的核心，控制细胞周期停滞的机制是细胞凋亡的关键。 区别尤其重要。细胞周期退出在癌发生中也是至关重要的，它被绕过， 以及在伤口愈合和再生中，其被逆转以允许重新增殖。细胞周期 退出已经在细胞培养和几种模式生物体内进行了研究， 细胞周期调控装置的分化信号仍然知之甚少。没有一般范式 解释了细胞分化与G1期阻滞的普遍偶联。这个建议是研究细胞 果蝇在三种特征明显的环境中分化时的周期退出：胚胎，翅膀和 眼睛我们将检验分化信号主要抑制细胞周期转录的假说 通过E2F/RB非依赖性机制控制基因。在目标1中，我们操纵已知细胞的活性， 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 基因表达在退出过程中。在目的2中，我们研究了转录调控区的转录， 关键的细胞周期控制基因，细胞周期蛋白E，以确定顺式作用元件，并最终反式作用因子， 在分化时介导其沉默。在目标3中，我们在果蝇中进行遗传筛选以识别新基因 对细胞周期退出有重要作用。综合结果应该可以区分出 在文献中提出的细胞周期退出的合理解释，确定新的基因产物，介导 细胞周期退出，并提供了一个工作模式，为未来的研究如何分化信号接口， 细胞周期控制装置。因为协调组织模式的遗传网络， 分化和细胞周期控制在果蝇和人之间是保守的，本文获得的结果 应该为正在进行的人类发育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.