Cellular correlates of proneural and Notch-delta gene expression in the regenerating zebrafish retina.

Fish can regenerate retinal neurons following ocular injury. Evidence is mounting that astrocytic glia function as inducible, regenerative stem cells in this process, but the underlying molecular events that enable neuronal regeneration are comparatively unclear. In the current study gene array, quantitative real-time PCR, in situ hybridization, and immunohistochemical approaches were used to identify, in the damaged retina of adult zebrafish, correlations between transcriptional events and entry into the cell cycle by Müller cells, a type of astrocytic cell present in all vertebrate retinas that is a candidate 'stem cell' of regenerated neurons. A proneural gene (achaete-scute homolog 1a, ash1a) and neurogenic components of the Notch signaling pathway, including notch3 and deltaA, were implicated. An injury-induced, enhanced expression of ash1a was observed in Müller cells, which is hypothesized to contribute to the transition of these cells, or their cellular progeny, into a notch3-expressing, regenerative progenitor. A model of vertebrate retinal repair is suggested in which damage-induced expression of proneural genes, plus canonical Notch-Delta signaling, could contribute to retinal stem cell promotion and subsequent regenerative neurogenesis.