Ascl1a regulates Müller glia dedifferentiation and retina regeneration via a Lin-28-dependent, let-7 miRNA signaling pathway

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 Müller glia (MG) dedifferentiation 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 MG within 6 hrs following retinal injury and are necessary for MG dedifferentiation. We demonstrate that Ascl1a is necessary for lin-28 expression and that Lin-28 suppresses let-7 miRNA expression. Furthermore we show that let-7 represses expression of regeneration-associated genes like, ascl1a, hspd1, lin-28, oct4, pax6b and c-myc. Interestingly, hspd1, oct4 and c-myc(a) exhibit basal expression in the uninjured retina and let-7 may inhibit this expression to prevent premature MG dedifferentiation. The opposing actions of Lin-28 and let-7 miRNAs on MG differentiation/dedifferentiation are similar to that of embryonic stem cells3 and suggest novel targets for stimulating MG dedifferentiation and retina regeneration in mammals.