Plagl2 unlocks the latent regenerative potential of Müller glia in the adult mouse retina

Summary 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 Plagl2, which has been demonstrated to rejuvenate aged neural stem cells, was 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 found that Plagl2 drove regulated rounds of MG cell cycle re-entry, while N-methyl-D-aspartate-induced retinal injury further promoted the acquisition of neurogenic competence toward inner nuclear layer neuronal identities. These findings identify Plagl2 as a novel rejuvenator of mammalian MG and support the general principle that reprogramming modules can be redeployed across cell types, offering new avenues for unlocking regenerative potential in otherwise non-regenerative tissues. Competing Interest Statement A patent application (PCT/JP2024/ 45989) has been filed by RIKEN.