The miR-216a-Dot1l Regulatory Axis Is Necessary and Sufficient for Müller Glia Reprogramming during Retina Regeneration

Abstract

Summary: Unlike the adult mammalian retina, Müller 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 Dot1l, which is upregulated in proliferating MG after retinal damage. Loss-of-function experiments show that Dot1l is necessary for MG reprogramming and mediates MG proliferation downstream of miR-216a. We further demonstrate that miR-216a and Dot1l 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. : Unlike the adult mammalian retina, Müller glia in the adult zebrafish retina are able to reprogram into a stem cell-like state and give rise to multipotent progenitor cells upon retinal damage. Kara et al. show that miR-216a suppression stimulates Müller glia reprogramming through upregulation of the H3K79 methyltransferase Dot1l and activation of Wnt/β-catenin signaling. Keywords: zebrafish, retina, regeneration, Müller glia, reprogramming, miRNA, Dot1l, Wnt