Control of Cell Proliferation and Differentiation in the Developing Retina

在正常的视网膜发育过程中，细胞的增殖和分化受到协调调节。 然而，控制细胞增殖和分化的分子机制并不是 为人所知。这项资助的目标是研究发育信号通路的机制 细胞内源性转录因子参与调控细胞的生长、增殖和分化 正在发育视网膜的果蝇。正在发育视网膜的果蝇非常适合 由于细胞生长、增殖和分化的区域被很好地刻画 与不同信号通路和细胞内在转录的特征区结合 因素，以及果蝇系统中可用的大量工具。 Notch信号是一种保守的发育信号通路，在眼睛中具有不同的作用 从细胞增殖、分化到决定细胞命运的各种发育。有趣的是， 在发育中的视网膜不同区域激活Notch信号导致不同的结果 信号诱导发育中视网膜前部的细胞生长和增殖，但诱导 就在形态发生沟前面的细胞分化。我们假设，人类的独特能力 Notch信号诱导其靶分子在发育中的视网膜不同区域表达 受Notch和其他信号通路或区域特异性因子之间的相互作用控制，并且 不同靶点的表达介导Notch信号在诱导细胞中的不同作用 在发育中的视网膜不同区域的增殖或分化。来检验这些假说，并 阐明发育中的视网膜中细胞增殖和分化的控制机制， 我们有以下三个具体目标：(1)研究Notch的分子机制 信号调节发育中的视网膜的细胞周期；(2)研究 Notch信号促进细胞生长和增殖的能力受到控制；(3)表征 果蝇视网膜发育过程中ATO表达启动的调控机制。 我们的长期目标是深入了解细胞的增殖和分化 视网膜发育，这可能会导致在预防方面开发新的方法， 诊断和治疗视网膜疾病以及其他人类疾病与细胞增殖或 分化缺陷。

Cell proliferation and differentiation is coordinately regulated during normal retinal development. However, the molecular mechanisms by which cell proliferation and differentiate 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 differentiationin 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 intrinsictranscriptional 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.