cxcl18b-defined transitional state-specific nitric oxide drives injury-induced Müller glia cell-cycle re-entry in the zebrafish retina

In lower vertebrates, retinal Müller glia (MG) exhibit a life-long capacity of cell-cycle re-entry to regenerate neurons following the retinal injury. However, the mechanism driving such injury-induced MG cell-cycle re-entry remains incompletely understood. Combining single-cell transcriptomic analysis andin-vivoclonal analysis, we identified previously undescribedcxcl18b-defined MG transitional states as essential routes towards MG proliferation following green/red cone (G/R cone) ablation. Microglial inflammation was necessary for triggering these transitional states, which expressed the gene modules shared by cells of the ciliary marginal zone (CMZ) where life-long adult neurogenesis takes place. Functional studies of the redox properties of these transitional states further demonstrated the regulatory role of nitric oxide (NO) produced byNos2bin injury-induced MG proliferation. Finally, we developed a viral-based strategy to specifically disruptnos2bincxcl18b-defined MG transitional states and revealed the effect of transitional state-specific NO signaling. Our findings elucidate the redox-related mechanism underlying injury-induced MG cell-cycle re-entry, providing insights into species-specific mechanisms for vertebrate retina regeneration.