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E. C. McDonald, T. A. Cook; Differential Functions for Otd, Otx2, and Crx during Fly Photoreceptor Development and Maintenance. Invest. Ophthalmol. Vis. Sci. 2009;50(13):1305.
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© ARVO (1962-2015); The Authors (2016-present)
From flies to humans, Orthodenticle (Otd)-related homeodomain transcription factors contribute to multiple aspects of eye development. Vertebrates encode three Otd-related factors, Otx1, Otx2 and Crx, while Drosophila encodes a single factor, Otd. Otx2 and Crx are expressed in all developing and mature photoreceptors, and Otx2 or Crx mutations are associated with a variety of photoreceptor degenerative diseases. Otd also controls photoreceptor morphogenesis and differential activates and represses distinct opsins in different photoreceptor subclasses. Here, we examined whether Otd is important to prevent retinal degeneration, and mapped regions within Otd necessary for its different functions during photoreceptor development. We also tested human Otx2 and Crx for their ability to replace some or all of Otd’s function in the Drosophila eye.
Using an in vivo genetic system, we replaced endogenous Otd protein with different Otd/Otx-encoding genes in an eye-specific Otd mutant background. Various deletion constructs of Otd, and full-length human Otx2 and Crx were then tested for their ability to rescue photoreceptor development, cell-type specific opsin activation and repression. In addition, photoreceptor integrity was analyzed after in flies raised in constant dark or light for 12 days.
In addition to its previously defined roles, we find that Otd is also important for preventing opsin co-expression and maintaining photoreceptor integrity during age-related and light-induced retinal degeneration. At least four independent subdomains within Otd selectively contribute to its different functions during photoreceptor development, and different domains contribute to Otd’s ability to regulate photoreceptor morphogenesis vs maintenance. Interestingly, Otx2 and Crx contribute to distinct but overlapping aspects of Otd function in the fly eye: each rescue photoreceptor morphogenesis, but differentially contribute to cell-specific opsin regulation. Ongoing studies are will test their ability rescue photoreceptor degeneration.
Our studies identify new roles for Otd during photoreceptor development and reveal that its different functions can be genetically isolated. In addition, human Otx2 and Crx share functional conservation with Otd but do not function redundantly in the fly eye. Thus, the Drosophila eye provides a new model for dissecting distinct genetically conserved roles for Otx2 and Crx during eye development.
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