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如何整合来自多个信号通路的指令并以适当的方式作出反应的机制。在这种情况下，磷酸化和去磷酸化等翻译后修饰为响应特定信号输入动态调节转录因子活性提供了多种策略。然而，这些修饰协调调节转录因子功能、与基础转录机制的相互作用以及染色质结构改变以实现上下文特异性输出的机制仍然知之甚少。果蝇特别适合解决复杂的发育问题，因为遗传学、分子生物学、生物化学、细胞生物学和基因组学方法可以很容易地结合在一起。由于发育信号机制在进化过程中一直高度保守，对果蝇分子电路的了解将从根本上推进我们对细胞命运如何被指定和维持，以及为什么调控不当导致哺乳动物癌症和疾病的理解。

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.