Mycb and Mych stimulate Müller glial cell reprogramming and proliferation in the uninjured and injured zebrafish retina.

Abstract

In the injured zebrafish retina, Müller glial cells (MG) reprogram to adopt retinal stem cell properties and regenerate damaged neurons. The strongest zebrafish reprogramming factors might be good candidates for stimulating a similar regenerative response by mammalian MG. Myc proteins are potent reprogramming factors that can stimulate cellular plasticity in differentiated cells; however, their role in MG reprogramming and retina regeneration remains poorly explored. Here we report that retinal injury stimulates mycb and mych expression and that although both Mycb and Mych stimulate MG reprogramming and proliferation, only Mych enhances retinal neuron apoptosis. RNAseq analysis of Wt, mychmut, and mycbmut fish revealed Mycb and Mych regulate ∼40% and ∼16%, respectively, of the genes contributing to MG's regeneration-associated transcriptome. Of these genes, those that are induced are biased towards regulating ribosome biogenesis, protein synthesis, DNA synthesis, and cell division which are the top cellular processes regulated by retinal injury and this suggests Mycb and Mych are potent MG reprogramming factors. Consistent with this, forced expression of either of these proteins is sufficient to stimulate MG proliferation in the uninjured retina.