Plagl2 reprograms adult mouse retinal Müller glia for proliferation and injury-enhanced neurogenic competence.

Abstract

Müller glia (MG) in the adult mammalian retina have long been recognized as a potential endogenous source for the regeneration of lost retinal neurons. However, existing MG reprogramming strategies yield an incomplete regenerative response by favoring either proliferation or neurogenic differentiation. Here, we show that the zinc-finger transcription factor gene Plagl2, previously shown to reactivate quiescent neural stem cells, is sufficient to reprogram adult mouse MG into a progenitor-like state with coupled proliferative and neurogenic competence. Using histology, time-lapse imaging, and single-cell transcriptomics, we find that Plagl2 drives regulated rounds of MG cell cycle re-entry, while N-methyl-D-aspartate-induced retinal injury further promotes the acquisition of neurogenic competence biased toward inner nuclear layer neuronal identities. These findings indicate that Plagl2 regulates mammalian MG reprogramming, and supports a broader approach to tissue regeneration through the adaptation of reprogramming modules across distinct cell types.