CELL/CELL SIGNALING IN EMBRYONIC AND RETINAL DEVELOPMENT

Whitehead Institute For Biomedical Res, Cambridge MA

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Abstract

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.