Unlike mammals, teleost fish mount a robust regenerative response to retinal injury that culminates in restoration of visual function1,2. This regenerative response relies on dedifferentiation of Müller glia into a cycling population of progenitor cells. However, the mechanism underlying this dedifferentiation is unknown. Here, we report that genes encoding pluripotency factors are induced following retinal injury. Interestingly, the proneural transcription factor, Ascl1a, and the pluripotency factor, Lin-28, are induced in Müller glia within 6 h following retinal injury and are necessary for Müller glia dedifferentiation. We demonstrate that Ascl1a is necessary for lin-28 expression and that Lin-28 suppresses let-7 microRNA (miRNA) expression. Furthermore, we demonstrate that let-7 represses expression of regeneration-associated genes such as, ascl1a, hspd1, lin-28, oct4, pax6b and c-myc. hspd1, oct4 and c-myca exhibit basal expression in the uninjured retina and let-7 may inhibit this expression to prevent premature Müller glia dedifferentiation. The opposing actions of Lin-28 and let-7 miRNAs on Müller glia differentiation and dedifferentiation are similar to that of embryonic stem cells3 and suggest novel targets for stimulating Müller glia dedifferentiation and retinal regeneration in mammals.
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We thank D. Hyde for sharing gfap:gfp transgenic fish, R. Thompson, D. Turner and M. Uhler for sharing expression vectors and reagents, J. Beals for help with confocal microscopy, the UM Flow Cytometry Core for help purifying GFP-labelled Müller glia, V. Kapuria for help with western blots; B. R. Wilfred and D. Turner for advice on miRNAs, P. Macpherson for help with statistics, T. Melendez for expert care of fish and D. Turner, J. Parent and members of the Goldman lab for their support and comments on this work. This work was supported by funds from the NIH NEI RO1 EY018132 (to D.G.) and NIH NICHD T32HD007507 (to R.R.).
The authors declare no competing financial interests.
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Ramachandran, R., Fausett, B. & Goldman, D. Ascl1a regulates Müller glia dedifferentiation and retinal regeneration through a Lin-28-dependent, let-7 microRNA signalling pathway. Nat Cell Biol 12, 1101–1107 (2010). https://doi.org/10.1038/ncb2115
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