Cells in a developing organism interact extensively with each other to acquire their correct fates, positions and orientations. These interactions are mediated by several signaling proteins, including the Frizzled cell surface molecules that act as receptors for secreted Wnt proteins. The mechanism of signal transduction of the Frizzled receptors is poorly understood. Some members of this receptor family can interact with several ligands, leading to different effects on target cells. It is not known how specificity between ligands, receptors and signal transduction components is determined. The proposed work aims at a better understanding of the mechanisms and the specificity of signaling by Frizzleds. It will focus on two different members of this receptor family in Drosophila: frizzled and frizzled2. As part of these studies, forward genetic screens will be performed to generate frizzled gene mutations in Drosophila. These include loss-of function- mutations to examine the requirements for these genes during development, and gain-of-function mutations that convert the receptor to a ligand-independent state. This mutational analysis will be complemented by experiments addressing genetic interactions between Frizzleds and other Drosophila genes. Finally, the affinity of binding between various Frizzled proteins and their Wnt ligands will be measured in a quantitative way. Given the widespread activity of Frizzled and Wnt molecules during animal development, these studies should produce important information on mechanisms of embryogenesis, including vertebrate development. Moreover, as many components of Wnt signaling are implicated in human tumors, this work is also relevant to our understanding of carcinogenesis.
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