| The Hedgehog (Hh) family of secreted proteins play important roles in multiple aspects of development in both invertebrates and vertebrates. In Drosophila, the embryonic segments and the larval imaginal discs are both patterned by Hh and offer excellent model systems to study the mechanisms of Hh signal transduction.;Previous genetic studies have placed the zinc finger protein Cubitus interruptus (Ci), homolog of the vertebrate Gli proteins, as a downstream effector of the Hh signal transduction pathway. In the absence of Hh signal, Ci is cleaved to generate a truncated nuclear form capable of transcriptional repression. Hh signaling up-regulates the activity of the full-length Ci protein, leading to induction of downstream target genes including patched and decapentaplegic. A number of molecules have been implicated in the regulation of Ci. Mutations in these molecules lead to changes in Ci protein level, the extent of Ci proteolysis and the expression of Ci target genes.;In this dissertation, genetic approaches are combined with biochemical and tissue culture analysis to examine the regulation of Ci stability, subcellular distribution and activity. For the regulation of each aspect of Ci metabolism, the role of Hh signaling and that of several Hh signal transduction pathway components were studied. The data presented here demonstrate that in vivo, two thresholds of Hh activity regulate distinct aspects of Ci metabolism, probably through differential stimulation of Hh signaling cascade components. The kinesin-related molecule Costal-2 appears to have a central role in the regulation of Ci by Hh. The different responses of Ci to different levels of Hh activity provide a mechanism by which the gradient of Hh can be translated into spatial domains of gene expression in a precise fashion. |
