During the development of multicellular organisms, cell proliferation is tightly regulated by intrinsic and extrinsic cues, generating a spatiotemporal cell cycle pattern. For instance, cell cycles are very rapid during early embryogenesis, resulting in a sufficient number of cells for tissue formation. In contrast, cells that are going to differentiate usually arrest the cell cycle in G1 phase and subsequently enter the quiescent state (G0). Failure to maintain active cell cycles during early embryogenesis and to arrest the cell cycle before differentiation will cause destructive effects on tissue development and homeostasis. Since cells usually arrest in G1, an important decision step in the cell cycle is whether the cell stays in G1 phase or enters S phase. When G1 cells enter S phase, positive cell cycle regulators such as Cyclin E, RnrS, PCNA, and DNA polymerase are coordinately induced by the family of the E2F transcription factors. In Drosophila, these genes are regulated by a single E2F (E2F1). During the early embryogenesis of Drosophila, E2F1-target genes are expressed ubiquitously, facilitating the rapid cell cycles. Later in embryogenesis, E2F1-target genes are downregulated before cells arrest in G1. This implies that during embryogenesis developmentally-regulated E2F1 activity causes this characteristic cell cycle pattern. In this thesis, we show that the initial downregulation of E2F1-target genes is preceded by the developmentally-regulated onset of E2F1 destruction. Furthermore, we discovered that DNA replication induces E2F1 destruction in a PCNA-, Cul4-, and Cdt2-dependent manner. Expression of a stabilized form of E2F1 in the larval wing disc caused apoptosis and disrupted adult wing morphology, while expression in the larval salivary gland arrested the endocycle, a variant G1-S cell cycle that lacks mitosis and results in polyploidy. Taken together, our data suggests the existence of a robust negative feedback mechanism where E2F1 induces DNA replication, which in turn downregulates E2F1 by proteolysis, and this negative feedback loop is required for normal development of Drosophila
