The function of the visual system is to form images in the brain. Correct specification and patterning of the photoreceptor neurons within the retina are a prerequisite for precise retinotopic axonal projections and image formation. The Drosophila eye serves as paradigm for many aspects of eye development, retinal biology and disease. The Drosophila retina is composed of a stereo-typed array of about 800 ommatidia, or unit eyes, each containing a precise arrangement of 8 photoreceptor neurons. The establishment of this precise arrangement requires the interplay of several signaling pathways and transcription factors, all of which are conserved and largely share equivalent functions in the mammalian eye. The correct specification of two of the photoreceptors, R3 and R4, requires an interplay of the Wnt/Frizzled (Fz)/planar cell polarity (PCP) and Notch signaling pathways. Strikingly, the second Fz mediated pathway, canonical (?-Catenin (Cat) signaling, causes photoreceptor cell death and reduction of eye size. As the Fz receptor and (at least) one effector (Dsh) are shared between Fz/|?-Cat and Fz/PCP signaling activating distinct effectors downstream of Dsh, correct regulation of signaling specificity is very critical for normal eye development. The regulation of this signaling specificity is only poorly understood. The scope of this application is to define the sequence elements with the Fz receptor that mediate the specific signaling outcome, and to define the respective modifications on the Dsh protein that distinguish between the Fz/|?-Cat and Fz/PCP pathways. Similarly, we will determine the cross-regulatory interactions between Fz/PCP and Notch signaling. A combination of cell culture and biochemical experiments and in vivo studies in the eye will be utilized to achieve these goals. In the human eye, Fz signaling is associated with diseases like Familial Exudative Vitreoretinopathy (FEVR) and the Norrie Disease. Several components of the Fz and Notch pathways are also critically linked to cancer and are associated with stem cell biology. Thus the information acquired in this application will advance our understanding of photoreceptor specification and eye diseases, and will also be of medical relevance in other areas, including stem cell biology. ? ?
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