Single-cell RNA sequencing unravels the transcriptional network underlying zebrafish retina regeneration

In the lesioned zebrafish retina, Muller glia produce multipotent retinal progenitors that generate all retinal neurons, replacing lost cell types. To study the molecular mechanisms linking Muller glia reactivity to progenitor production and neuronal differentiation, we used single-cell RNA sequencing of Muller glia, progenitors and regenerated progeny from uninjured and light-lesioned retinae. We discover an injury-induced Muller glia differentiation trajectory that leads into a cell population with a hybrid identity expressing marker genes of Muller glia and progenitors. A glial self-renewal and a neurogenic trajectory depart from the hybrid cell population. We further observe that neurogenic progenitors progressively differentiate to generate retinal ganglion cells first and bipolar cells last, similar to the events observed during retinal development. Our work provides a comprehensive description of Muller glia and progenitor transcriptional changes and fate decisions in the regenerating retina, which are key to tailor cell differentiation and replacement therapies for retinal dystrophies in humans.