The function of the visual system is to form images in the brain. Correct photoreceptor neuron specification, patterning and morphogenesis within the retina are prerequisites for correct retinotopic axonal projections and thus image formation. The Drosophila eye serves as an excellent paradigm for many aspects of eye development, retinal biology, and disease. It is composed of a stereo-typed array of 700-800 ommatidia, or unit eyes/facets, each containing a precise arrangement of 8 photoreceptor neurons, R-cells. Establishment of their fates and their ordered arrangement requires an interplay of several signaling pathways, which are conserved with similar functions during mammalian eye development. Precise retinal arrangement and morphogenesis requires a distinction of two subtypes of photoreceptors, R3 and R4, via an exquisite regulation and interplay of canonical Wnt-signaling, the Wnt/Frizzled(Fz)/planar cell polarity (PCP) pathway, and Notch (N)-signaling. Wnt/?-catenin signaling sets up the D/V-axis, needed by Wnt/Fz-PCP signaling to correctly induce R3/R4 neurons. Wnt-PCP signaling in turn has to both activate N-signaling in neighboring cells to induce R4, and simultaneously inhibit N-activity in R3. Thus a highly regulated Wnt/Fz and N-pathway cross-regulation determines photoreceptor patterning and morphogenesis of the retina. Our prelim. data identified a novel cross-talk between Wnt and N-signaling at the level of Dsh/Dvl and the N-dependent transcription factor Su(H), CSL in mammals. We have also uncovered a novel function for non-canonical N-signaling in cell adhesion and morphogenesis, mediated by Abl kinase. The scope of this application addresses interactions among the Wnt and N pathways and functional dissection of the non-canonical N activity in the retina.
The Specific Aims are: (1) To dissect a novel inhibitory cross-talk between the Wnt/Fz-Dsh and N-signaling and the associated effects on R3/R4 specification; (2) To address the function of non-canonical N/Abl-signaling during retinal patterning in R4 cell motility and ommatidial rotation; and (3) To use live imaging to extract specific roles of N/Abl signaling in tissue morphogenesis and associated biophysical properties of cell adhesion.
These Aims are well integrated and based on exciting hypotheses and prelim. data, including analyses of several kinases and N- signaling read-outs (Aims 1 and 2), and the role of the N/Abl activity in the regulation of junctional remodeling and morphogenesis (Aim 3). A combination of in vivo studies, cell culture and biochemical experiments, and genetics/genomics will be utilized together with newly developed live imaging protocols to achieve these goals. In the human eye, Wnt-Fz and Notch signaling are associated with many diseases and, moreover, several components are associated with congenital ciliopathies affecting retinal function. Thus the information acquired here will advance our understanding of retinal biology and will also be of medical relevance in disease areas.
Correct photoreceptor neuron specification, patterning, and morphogenesis in the retina are essential for vision. Understanding the Wnt/Frizzled (Fz)-PCP and Notch-signaling pathway read-outs and their interactions in this context has important implications in both vision research and other diseases, including ciliopathies, ranging from retinal degeneration, mental retardation and cancer to angiogenesis defects. This application addresses the regulation of these pathways in photoreceptor specification and retinal patterning.
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