Control of Cell Proliferation and Differentiation in the Developing Retina

描述(申请人提供)：这项研究的长期目标是阐明动物发育过程中控制细胞增殖或分化的分子机制。具体地说，这项研究将以发育中的果蝇视网膜为模型系统，研究发育信号通路(如Notch)与细胞内在转录因子(如无性素和无子体)相互作用控制细胞增殖和分化的机制。无核黄体激素是一个转录因子家族，在光感受器细胞分化的启动过程中是必需的。在发育中的眼睛诱导无张力需要Notch信号，这是一种保守的发育途径，在正常发育中具有不同的作用。Notch信号也参与了细胞周期的调控，但激活Notch信号会在某些类型的细胞中诱导细胞增殖，而在另一些类型的细胞中诱导细胞周期停滞和分化。Notch信号导致不同细胞类型的细胞增殖或细胞周期停滞的机制仍不清楚。果蝇发育中的视网膜提供了一种独特的发育系统，非常适合于这一研究，因为它具有良好的细胞增殖模式和发育信号，而且很容易产生在发育过程中可以准确识别的功能细胞克隆的丧失或获得。此外，针对Notch的三个细胞增殖和分化靶点的眼睛特异性增强剂已经被确定。在这项资助中，我们使用这些试剂来研究Notch信号调节果蝇视网膜发育中细胞增殖的机制。具体地说，我们建议(1)确定Notch信号在细胞周期调节和细胞周期蛋白E和Dacapo调节中的作用；(2)确定无性系和无性系在协调细胞周期停滞和细胞分化中的作用；(3)确定Notch和其他发育信号通路调节无性系表达和细胞增殖或分化的机制。由于Notch通路在哺乳动物系统中是保守的，在包括癌症在内的人类疾病中经常被解除调控，因此本研究将为了解Notch信号在发育调节的细胞增殖中的作用以及在人类癌症中的作用提供重要的新视角。

DESCRIPTION (provided by applicant): The long term objective of this research is to elucidate the molecular mechanisms by which cell proliferation or differentiation is controlled in animal development. Specifically, the research in this grant will use the Drosophila developing retina as a model system to investigate the mechanisms by which developmental signaling pathways such as Notch and cell intrinsic transcription factors such as atonal and daughterless interact to control cell proliferation and differentiation. Atonal is a bHLH family of transcription factor that is required for the initiation of photoreceptor cell differentiation. The induction of atonal in the developing eye requires Notch signaling, a conserved developmental pathway that has diverse roles in normal development. Notch signaling has also been implicated in regulating the cell cycle, however activation of Notch signaling will induce cell proliferation in some cell types while induce cell cycle arrest and differentiation in others. The mechanisms by which Notch signaling leads to cell proliferation or cell cycle arrest in distinct cell types remains elusive. The Drosophila developing retina provides a unique developmental system that is ideally suited for this investigation because of the well-characterize patterns of cell proliferation and the developmental signaling and because of the ease of generating loss or gain of function cell clones that can be precisely identified during development. Furthermore, the eye-specific enhancers for three of Notch's cell proliferation and differentiation targets have been identified. In this grant, we use these reagents to investigate the mechanism by which Notch signaling regulates cell proliferation in the Drosophila developing retina. Specifically, we propose to (1) determine the role of Notch signaling in cell cycle regulation and in the regulation of cyclin E and Dacapo; (2) determine the role of atonal and daughterless in coordinating cell cycle arrest with cell differentiation; and (3) determine the mechanism by which Notch and other developmental signaling pathways regulate atonal expression and cell proliferation or differentiation. Since the Notch pathway is conserved in mammalian systems and is often deregulated in human diseases including cancers, the proposed studies will provide significant new insight into the roles of Notch signaling in developmentally regulated cell proliferation as well as in human cancers.