Mammalian retinas fail to regenerate because Müller glia (MG) do not reprogram into retinal progenitor cells (RPCs) after injury; cold-blooded vertebrates like zebrafish retain that capacity. Prox1, a prospero-related homeobox transcription factor that enforces cell-cycle exit during neurogenesis, is found to accumulate in MG of degenerating human and mouse retinas but not in regenerating zebrafish. In mouse models of photoreceptor and inner retinal cell loss (MNU, intensive light exposure, NMDA, and Crx-CreERT2;R26 DTA/+ tamoxifen-driven PR ablation), Prox1 levels rise in MG proportionally to injury severity. Crucially, Prox1 is not produced endogenously by mouse MG; instead it is transferred from neighboring retinal neurons via intercellular protein transfer, a property of homeodomain proteins.
Interrupting that intercellular transfer restores MG regenerative competence: blocking Prox1 entry into MG reprograms them into proliferative MG-derived RPCs in injured mouse retinas. Delivering an adeno-associated virus encoding an anti-Prox1 antibody that sequesters extracellular Prox1 promotes retinal neuron regeneration and delays vision loss in a retinitis pigmentosa model. Complementary experiments show that injecting recombinant Prox1 into zebrafish suppresses MGPC proliferation, demonstrating that exogenous Prox1 is a functional inhibitor of MG reprogramming. These results identify extracellular Prox1 as a barrier to MG-mediated retinal regeneration and nominate anti-Prox1 strategies as a therapeutic avenue to restore regeneration in mammals.
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