The Hh pathway regulates cell growth and proliferation during Drosophila development. W. Du , M. Duman-Scheel , L. Weng. Ben May Inst CA Res/Molec Onc, Univ Chicago, Chicago, IL.

   The Retinoblastoma (RB) pathway is thought to act as a signal integrator that receives multiple positive and negative growth signals and in turn controls whether a cell should proliferate or remain quiescent. It is largely unknown how the RB pathway (including the tumor suppressor gene RB, its regulators, such as Cyclin D, and its targets, the E2F transcription factors) interacts with other signal transduction pathways. Using the Drosophila eye as a model system, we have studied the developmental function of RBF, the Drosophila RB family homolog, and carried out genetic screens to identify genes that are regulators or targets of the RB pathway. Overexpression of RBF in the developing eye inhibits expression of E2F target gene, delays the completion of S phase, and disrupts normal eye development. A mutation in patched (ptc), a negative regulator of the Hedgehog (Hh) signaling pathway, suppresses the RBF overexpression phenotype. This finding suggests that Hh, a key regulator of a variety of developmental processes, regulate cell proliferation through the RB pathway. We show that overexpression of Cubitus interruptus (Ci), a transcription factor activated by Hh signaling, induces ectopic S phase in the developing eye, and that blocking Hh signaling in the eye disrupts S phase in the second mitotic wave. Furthermore, we show that increasing or decreasing Hh signaling through the overexpression of Ci or Ptc affects cell growth and doubling time. A detailed analysis of the cell cycle targets of the Hh pathway, as well as the functional relationship between the Hh pathway and the RB pathway will be presented.