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J.M. Fadool, K. Alvarez–Delfin, A.C. Morris; Multiple Roles for Delta/Notch Signaling in Vertebrate Retinal Development . Invest. Ophthalmol. Vis. Sci. 2005;46(13):2440.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Delta/notch signaling has multiple roles during Drosophila eye development including lateral inhibition to regulate the number and spacing of R8 photoreceptors (PC), distinguishing R3 vs R4 PC fates and specifying, in combination with sevenless, the R7 PC. Homologues of notch and delta display complex expression patterns during vertebrate retinal development, however specific roles have been limited to lateral inhibition during ganglion cell specification and the promotion of radial glial cell maturation. The purpose of this project was to genetically and pharmacologically test for additional roles of delta/notch in the establishment of laminar vs mosaic patterning using the zebrafish (Danio rerio) as a model organism. Methods: Retinal development was examined in zebrafish mutant for the two neurogenic genes, deadly seven (des; notch1a) and mindbomb (mib; an E3 ubiquitin ligase essential for delta/notch signaling). Notch signaling was inhibited by treatment of embryos with the gamma secretase inhibitor DAPT. Immunolabeling and in situ hybridization with cell–specific probes were used to determine the effects upon lamination and mosaic patterning. Results: Mutation of notch1a initially resulted in delayed retinal development, however at later stages, lamination and mosaic arrangements were no different than controls suggesting compensation by other members of the family. Disruption of notch signaling in mib mutant larvae resulted in far more severe developmental defects. Most notably, only two retinal cell types matured in mib mutants, ganglion cells in the inner retina and PCs formed an outer nuclear layer. Unexpectedly, all of the cells in the ONL expressed genes typical of red cones, and the crystalline–like photoreceptor mosaic was absent. Even in the ventral retina where rods constitute a large proportion of the PCs, all expressed antigens consistent with specification as red cones. Pharmacological inhibition of notch signaling resulted in more modest disruption of retinal lamination. In addition to an increase in the number of ganglion cells, DAPT treatment blocked Müller cell maturation and the putative radial glia of the inner nuclear layer reentered the cell cycle. Conclusions: These data suggest several new roles for notch/delta signaling during vertebrate retinal development. First is an essential role in the specification and mosaic arrangement of PCs either through lateral inhibition to control the number and spacing of red cones or by directly specifying the other PC subtypes. Second, in Müller glial differentiation, notch signaling is required for cell cycle withdrawal prior to maturation.
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