In the mouse, the Microphthalmia-related Transcription Factor (Mitf) plays a critical role in the development of the retinal pigmented epithelium (RPE) of the eye. Mitf is one of the determinants of RPE identity and contributes to the proliferation, specification and differentiation of this tissue. In the fly, dMitf s expressed within the eye disc (the progenitor tissue that gives rise to the retina and surrounding head structures). Interestingly, it is expressed in the peripodial membrane (PM) a region of the disc epithelium that, similarly to the presumptive RPE region of the optic vesicle/cup, (a) does not itself form retina, (b) is juxtaposed to and continuous with the retinal epithelium, and (c) transiently expresses the fly homologues of two other transcription factors (Pax6 and Otx2) known to function in RPE formation. As shown here, dMitf controls proliferation in the eye disc can suppress retinal identity and may contribute to the specification of the non-neural portion of the epithelium. These striking similarities strongly suggest that RPE and PM cells are evolutionarily related and that a conserved Mitf genetic pathway functions during RPE and PM development. For these reasons, we propose to investigate the function(s) of dMitf during eye development in the Drosophila model system.
The specific aims proposed in this grant focus on two main areas: The analysis of dMitf function in eye disc development and the identification of additional components of the pathway. Through the detailed loss-of-function and gain-of-function studies proposed in the first two aims, we will establish how dMitf contributes to specification/differentiation of the PM and normal proliferation of the eye disc. In the last two aims and as a first step towards characterizing the dMitf pathway, we propose to identify additional components through yeast 2-hybrid and genetic-interaction screens. We believe that these approaches will lead to the identification of additional conserved factors that function with Mitf during eye formation in fly and vertebrates. Mutations in the mouse Mitf locus cause microphthalmia, pigmentation, bone and hearing defects and the RPE promotes proper survival and function of photoreceptor cells throughout life as well as influences retinal neurogenesis and lamination during development. These critical roles of the RPE in eye formation and function are highlighted by the significant number of diseases associated with genes specifically expressed or enriched in the RPE as well as by the link between RPE dysfunction and several eye diseases including age-related macular degeneration (AMD).
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