CELL/CELL SIGNALING IN EMBRYONIC AND RETINAL DEVELOPMENT

描述（改编自申请人摘要）：本研究的长期目标是了解发育中的细胞如何整合来自多种信号通路的指令并以适当的方式做出反应的机制。在所有多细胞生物的正常发育过程中，受体酪氨酸激酶介导的信号通路对有丝分裂、细胞命运规范和分化至关重要。在哺乳动物中，该通路的不受控制的活性与肿瘤的发生有关，并且该通路的几个组成部分，最著名的是GTPase， Ras，已被确定为致癌基因。Ras下游参与RTK信号事件的蛋白包括丝氨酸/苏氨酸激酶的丝裂原活化蛋白激酶（MAPK）家族。虽然基本的RTK/Ras/MAPK信号盒已被很好地理解，但对该途径下游靶点的性质以及这些效应物如何协调对RTK启动信号的特异性反应知之甚少。由于进化上保守的RTK通路在所有多细胞生物的发育过程中在许多不同的情况下反复使用，因此鉴定和功能表征这些下游效应物至关重要。这些研究将从根本上促进我们对正常发育和异常事件的理解，在这些异常事件中，对保守信号的不适当反应可能导致哺乳动物的肿瘤发生。果蝇特别适合解决复杂的发育问题，因为遗传、分子、生化和细胞生物学方法可以很容易地结合在一起。此外，由于控制基本发育过程的信号机制在进化过程中是高度保守的，因此在果蝇中使用的细胞-细胞通信的分子电路知识与哺乳动物发育的研究有关。在果蝇眼基因筛选中分离出三个新基因EY2-3、EY2-7和EY3-5，用于鉴定RTK信号通路的下游组分。本应用程序的具体目的是定义由这三个基因编码的蛋白质的特性，通过研究去除正常蛋白质功能的发育后果来确定它们在体内的作用，并研究它们在眼睛和胚胎中神经元和非神经元细胞类型分化期间参与RTK通路信号事件。这项研究将增强我们对RTK通路功能的理解，无论是在正常发育的背景下，还是在不适当的RTK信号可能是哺乳动物肿瘤发生的致病因素的情况下。

DESCRIPTION (Adapted from applicant's abstract): The long-term goal of this research is to understand the mechanisms whereby developing cells integrate instructions received from multiple signaling pathways and respond in a context-appropriate manner. The receptor tyrosine kinase mediated signaling pathway is critical for mitogenesis, cell fate specification and differentiation during normal development of all multicellular organisms. In mammals, uncontrolled activity of the pathway has been implicated in tumorigenesis and several components of the pathway, most notably the GTPase, Ras, have been identified as oncogenes. Proteins involved in RTK signaling events downstream of Ras include the mitogen-activated protein kinase (MAPK) family of serine/threonine kinases. While the basic RTK/Ras/MAPK signaling cassette is well understood, very little is known about the nature of the downstream targets of the pathway and how these effectors coordinate the specificity of response to RTK-initiated signals. Since the evolutionarily conserved RTK pathway is used reiteratively in many different contexts during the development of all multicellular organisms, identification and functional characterization of these downstream effectors is of critical importance. These studies will fundamentally advance our understanding of both normal development and aberrant events where inappropriate responses to conserved signals may lead to oncogenesis in mammals. Drosophila is particularly well suited to addressing complex developmental questions because of the ease with which genetic, molecular, biochemical and cell biological approaches can be combined. Furthermore, since signaling mechanisms controlling basic developmental processes were highly conserved in evolution, knowledge of the molecular circuitry of cell-cell communication used in Drosophila is relevant to the study of mammalian development. Three novel genes, EY2-3, EY2-7 and EY3-5, were isolated in a genetic screen in the Drosophila eye that was designed to identify downstream components of the RTK signaling pathway. The specific aims of this application are to define the properties of the proteins encoded by these three genes, to determine their in vivo role by studying the developmental consequences of removing normal protein function and to investigate their involvement in RTK pathway signaling events during the differentiation of both neuronal and non-neuronal cell- types in the eye and embryo. This research will enhance our understanding of RTK pathway function both in the context of normal development and in cases where inappropriate RTK signaling may be a causative factor in tumorigenesis in mammals.