Cell-Cell Signaling in Embryonic and Retinal Development

描述（由申请人提供）：本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当的方式响应的机制。在这种情况下，翻译后修饰，如磷酸化和去磷酸化提供了多功能的策略，用于动态调节转录因子的活性，以响应特定的信号输入。然而，这种修饰协调调节转录因子功能的机制，与基础转录机制的相互作用，以及染色质结构的改变，以实现特定的输出仍然知之甚少。果蝇特别适合解决复杂的发育问题，因为遗传，分子，生物化学，细胞生物学和基因组方法可以很容易地结合起来。由于发育信号机制在进化中高度保守，因此对果蝇中使用的分子电路的了解将从根本上促进我们对细胞命运如何指定和维持以及为什么失调会导致哺乳动物癌症和疾病的理解。 这一建议解决了核酪氨酸磷酸酶活性，由一个双重功能的转录因子和磷酸酶介导的假设，提供了一种新的策略，转录调控和信号整合。具体的目的是定义一个新的功能的转录辅激活剂的眼睛缺席作为磷酸酶，以确定磷酸酶活性是如何调节和协调与转录功能，并调查的生理背景下，眼睛缺席参与核磷酸化和去磷酸化事件。考虑到该提案中研究的蛋白质的进化保守程度，这项工作将为人类发育和疾病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.