MUTATIONAL ANALYIS OF FRIZZLED CLASS RECEPTORS IN HEDGEHOG &WNT/WINGLESS SIGNAL

The Frizzled (Fz) class of serpentine transmembrane proteins encode putative receptors involved in transducing both Hedgehog and Wnt proteins, intracellular signals which have diverse and conserved roles during animal development. Three Fz proteins have been identified in Drosophila: Fz, Fz2 and Smoothened (Smo). They have a common structure, including a conserved cystein rich extracellular domain (called the CRD for "cystein rich domain") which is believed to be a ligand binding domain and a conserved seven-pass transmembrane domain. Although there is some uncertainty about what ligands actually bind each of these putative receptors, our previous work indicates that Smo is an essential component of Hh signal transduction in Drosophila. The function of the Fz class of receptors is likely to be of significance for understanding skin diseases, particularly skin cancers. Indeed, defects in Hh signaling, especially conditions that lead to ectopic Hh expression, or ectopic activity of the Hh signal transduction pathway, have been shown to cause mammalian basal cell carcinomas. In this Pilot and Feasibility study, we propose genetic experiments to isolate and characterize new mutations which block, or constitutively activate, Fz receptors in Drosophila, with the goal of understanding how these receptors are normally regulated by ligand, and how they alter cellular behavior in response to ligand or mutations which alter their signal transducing properties.