The Drosophila segment polarity gene hedgehog (hh) encodes the founding member of a family of secreted proteins involved in organizing the development of body segments, limb, eyes, and other organ systems in vertebrates and invertebrates. Hh family members exert their biological influence through an evolutionarily conserved, yet poorly defined signal transduction cascade. The long-term goal of our research is to understand the molecular mechanism by which Hedgehog (Hh) signaling activity controls cell growth and patterning in animal development. We use Drosophila wing development as a model system to address how Hh signal is generated and interpreted to govern pattern formation. Our general approach is to identify novel signaling components by genetic screen and determine their mechanisms of action by a combination of genetic, molecular and biochemical analyses. Specifically, the proposed research is to investigate the mechanisms by which protein kinase A and Slimb negatively regulate Hh signal transduction, and to carry out genetic and molecular analyses of a novel Hh signaling component, central missing (cmn). Mutations in Hh signaling components are linked to numerous human disorders including developmental disorders and cancer. Thus studying the mechanisms by which PKA, Slimb and Cmn regulate Hh signal transduction should provide important insights into how Hh signaling activity is controlled during normal development and how it is deregulated in human disorders. Knowledge gained from the proposed study may provide new avenues for diagnosis and therapeutic intervention of cancers caused by mis-regulation of Hh signaling activity.