GENETIC ANALYSIS OF E2F FUNCTION DURING DEVELOPMENT

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Controlling the cell division cycle is an essential part of normal animal development. In proliferating tissues, progression through the cell cycle assures that cell division accompanies growth. In contrast, terminal differentiation is typically preceded by cell cycle arrest and the cessation of proliferation. The decision to proliferate or remain quiescent is most often made during the G1 phase of the cell cycle. Somatic cells must correctly manage this decision in order to properly maintain homeostasis. Such management requires regulation of the cell cycle machinery controlling the G1-S transition. This includes gene amplification of positive cell cycle effectors such as cyclin D1, and mutation of negative effectors such as tumor suppressors pRB and p16. These molecules are part of a molecular pathway that controls the cell cycle in response to both positive and negative extracellular effectors of cell growth. A major target of regulation of these molecules is the ES2F/DP family of heterodimeric transcription factors. E2F/DP/1/s control the expression of genes require for growth and DNA replication. Recent results indicate that perturbations of E2F/DP function both in vitro and in vivo can also be oncogenic. E2F/DP and its known upstream regulators are all conserved in Drosophila melanogaster, where we can apply sophisticated genetic approaches to an analysis of E2F/DP function. In Drosophila, dE2F/dDP is required for normal development. Thus, developmental signals that control cell fate may regulate growth and cell cycle progress via altering E2F/DP activity. The goals of this proposal are 1) to genetically identify novel Drosophila genes that regulate the activity of dE2F/dDP and therefore may regulate the G1-S transitions of the cell-cycle, and 2) to understand how dE2F/dDP regulates transcription in vivo and how this affects cell cycle control during development.