): The function of the visual system is to form images. Correct patterning of photoreceptor neurons in the retina is critical for their precise retinotopic axonal projections onto the optic lobes in the brain. Precise photoreceptor arrangement within the retinal epithelium is thus important. The Drosophila retina is a stereotyped pattern of about 800 ommatidia, or unit eyes, and the photoreceptor neurons within each ommatidium. The establishment of this precise arrangement serves as a paradigm to study epithelial planar polarity (often present in neuro-epithelial structures). It requires the Frizzled (Fz) receptor and its associated signaling pathway. Fz proteins are receptors for the Wg/Wnt growth factor family. Fz signaling regulates both early eye development and eye size, and the ommatidial arrangement within the retina. Fz uses distinct signaling pathways to achieve these different tasks. Wg/Fz signaling regulates eye size, whereas a distinct Fz-mediated signaling pathway regulates photoreceptor arrangement. It is important to achieve signaling specificity as these Fz functions lead to opposite responses: Wg/Fz signaling inhibits photoreceptor differentiation, whereas Fz/planar polarity signaling regulates the precise photoreceptor arrangement. The scope of this application is to identify the Fz domains that select between the two signaling cascades, and to identify the proteins that interact with the respective sequences. A combination of Drosophila in vivo studies and biochemical experiments will be used to achieve this goal. Several effectors of Fz have been identified and will be analyzed for their role in the selection between the two Fz signaling cascades. Wnt/Fz signaling has also been implicated in many forms of cancer and several of its components are proto-oncogenes. Thus the information acquired in this application will both advance our understanding of retinal patterning in the eye, and will also be of importance for the study of carcinogenesis.
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