Cell Proliferation/Differentiation in Developing Retina

描述（由申请人提供）：细胞增殖和分化在正常视网膜发育过程中受到协调调节。然而，控制细胞增殖和分化的分子机制尚不清楚。这项资助的目的是研究发育信号通路和细胞内在转录因子在果蝇发育视网膜中控制细胞生长、增殖和分化的机制。果蝇发育中的视网膜非常适合于所提出的研究，因为细胞生长，增殖和分化的良好特征区域与不同信号传导途径和细胞内在转录因子的良好特征区域相结合，并且因为果蝇系统中有大量可用的工具。 Notch信号传导是一种保守的发育信号传导途径，其在眼睛发育中具有多种作用，包括细胞增殖、分化和细胞命运决定。有趣的是，Notch信号在发育中的视网膜的不同区域中的激活导致不同的结果：Notch信号在发育中的视网膜的前部诱导细胞生长和增殖，但在形态发生沟之前诱导细胞分化。我们假设Notch信号传导诱导其靶点在发育中的视网膜的不同区域中表达的独特能力是由Notch与其他信号传导途径或区域特异性因子之间的相互作用控制的，并且不同靶点组的表达介导Notch信号传导在发育中的视网膜的不同区域中诱导细胞增殖或分化的不同作用。为了验证这些假说并阐明发育中视网膜细胞增殖和分化的调控机制，我们有以下三个具体目标：（1）研究Notch信号调控发育中视网膜细胞周期的分子机制;（2）研究Notch信号促进细胞生长和增殖的能力的调控机制;（3）研究果蝇视网膜发育过程中Ato表达起始的调控机制。 我们的长期目标是深入了解视网膜发育中的细胞增殖和分化，这将可能导致预防，诊断和治疗视网膜疾病以及其他具有细胞增殖或分化缺陷的人类疾病的新方法的发展。

DESCRIPTION (provided by applicant): Cell proliferation and differentiation is coordinately regulated during normal retinal development. However, the molecular mechanisms by which cell proliferation and differentiation are controlled are not known. The goal of this grant is to investigate the mechanisms by which developmental signaling pathways and cell intrinsic transcription factors interact in the control of cell growth, proliferation and differentiation in the Drosophila developing retina. The Drosophila developing retina is ideally suited for the proposed research because of the well-characterized zones of cell growth, proliferation, and differentiation in conjunction with the well-characterized zones of different signaling pathways and cell intrinsic transcriptional factors, and because of the large set of tools that are available in the Drosophila system. Notch signaling is a conserved developmental signaling pathway that has diverse roles in eye development ranging from cell proliferation, differentiation, and cell fate determination. Interestingly, activation of Notch signaling in different regions of the developing retina leads to different outcomes: Notch signaling induces cell growth and proliferation in the anterior of the developing retina but induces differentiation in cells just ahead of the morphogenetic furrow. We hypothesize that the distinct ability of Notch signaling to induce the expression of its targets in different regions of the developing retina is controlled by the interactions between Notch and other signaling pathways or region specific factors, and that the expression of distinct set of targets mediates the different effect of Notch signaling in inducing cell proliferation or differentiation in different regions of the developing retina. To test these hypotheses and to elucidate the mechanisms by which cell proliferation and differentiation is controlled in the developing retina, we have the following three Specific Aims: (1) To investigate the molecular mechanisms by which Notch signaling regulates the cell cycle in the developing retina; (2) To investigate the mechanisms by which the ability of Notch signaling to promote cell growth and proliferation is controlled; (3) To characterize the mechanism by which the initiation of Ato expression is controlled in the Drosophila developing retina. Our long-term objective is to achieve a deep understanding of cell proliferation and differentiation in retinal development, which will potentially lead to the development of new approaches in the prevention, diagnosis, and treatment of retinal diseases as well as other human diseases with cell proliferation or differentiation defect.