Cell-Cell Signaling in Embryonic and Retinal Development

描述(由申请人提供)：这项研究的长期目标是阐明细胞整合来自多个信号通路的指令并以适合背景的方式做出反应的机制。在这种背景下，翻译后修饰，如磷酸化和去磷酸化，提供了多种策略来动态调节转录因子的活性，以响应特定的信号输入。然而，这种修饰如何协调调节转录因子的功能、与基础转录机制的相互作用以及染色质结构的变化以实现上下文特定的输出的机制仍然知之甚少。果蝇特别适合于解决复杂的发育问题，因为遗传、分子、生化、细胞生物学和基因组方法可以很容易地结合在一起。由于发育信号机制在进化中高度保守，了解果蝇使用的分子电路将从根本上提高我们对细胞命运是如何指定和维持的，以及为什么调控不当会导致哺乳动物癌症和疾病的理解。 这一建议解决了这样的假设，即核酪氨酸磷酸酶活性由双功能转录因子和磷酸酶介导，为转录调控和信号整合提供了一种新的策略。其具体目的是定义作为磷酸酶缺失的转录辅活化子眼睛的新功能，确定磷酸酶活性如何与转录功能调节和协调，并调查缺失眼睛参与核磷酸化和去磷酸化事件的生理背景。鉴于这一建议中研究的蛋白质在进化上的保守程度，这项工作将为人类发育和疾病潜在的基本信号机制提供新的见解。

DESCRIPTION (provided by applicant): The long-term goal of this research is to elucidate the mechanisms whereby cells integrate instructions from multiple signaling pathways and respond in a context-appropriate manner. In this context, post-translational modifications such as phosphorylation and dephosphorylation provide versatile strategies for dynamically modulating transcription factor activity in response to specific signaling inputs. However the mechanisms whereby such modifications coordinately regulate transcription factor function, interactions with the basal transcription machinery, and alterations in chromatin structure to achieve a context-specific output remain poorly understood. Drosophila is particularly well-suited to addressing complex developmental questions because of the ease with which genetic, molecular, biochemical, cell biological and genomic approaches can be combined. Because developmental signaling mechanisms have been highly conserved in evolution, knowledge of the molecular circuitries used in Drosophila will fundamentally advance our understanding of how cell fates are designated and maintained, and why misregulation results in cancer and disease in mammals. This proposal addresses the hypothesis that nuclear tyrosine phosphatase activity, mediated by a dual function transcription factor and phosphatase, provides a novel strategy for transcriptional regulation and signal integration. The specific aims are to define a new function for the transcriptional coactivator Eyes absent as a phosphatase, to determine how phosphatase activity is regulated and coordinated with transcriptional functions, and to investigate the physiological context in which Eyes absent participates in nuclear phosphorylation and dephosphorylation events. Given the extent of evolutionary conservation of the proteins studied in this proposal, this work will provide novel insights into fundamental signaling mechanisms underlying human development and disease.