The miR-216a-Dot1I Regulatory Axis Is Necessary and Sufficient for Muller Glia Reprogramming during Retina Regeneration

Unlike the adult mammalian retina, Muller glia (MG) in the adult zebrafish retina are able to dedifferentiate into a "stem cell"-like state and give rise to multipotent progenitor cells upon retinal damage. We show that miR-216a is downregulated in MG after constant intense light lesioning and that miR-216a suppression is necessary and sufficient for MG dedifferentiation and proliferation during retina regeneration. miR-216a targets the H3K79 methyltransferase Dot1I, which is upregulated in proliferating MG after retinal damage. Loss-of-function experiments show that Dot1I is necessary for MG reprogramming and mediates MG proliferation downstream of miR-216a. We further demonstrate that miR-216a and Dot1I regulate MG-mediated retina regeneration through canonical Wnt signaling. This article reports a regulatory mechanism upstream of Wnt signaling during retina regeneration and provides potential targets for enhancing regeneration in the adult mammalian retina.