Retinal Injury, Growth Factors, and Cytokines Converge on β-Catenin and pStat3 Signaling to Stimulate Retina Regeneration

Abstract

Summary: Müller glia (MG) in the zebrafish retina respond to retinal injury by generating multipotent progenitors for retinal repair. Here, we show that Insulin, Igf-1, and fibroblast growth factor (FGF) signaling components are necessary for retina regeneration. Interestingly, these factors synergize with each other and with heparin-binding EGF-like growth factor (HB-EGF) and cytokines to stimulate MG to generate multipotent progenitors in the uninjured retina. These factors act by stimulating a core set of signaling cascades (Mapk/Erk, phosphatidylinositol 3-kinase [PI3K], β-catenin, and pStat3) that are also shared with retinal injury and exhibit a remarkable amount of crosstalk. Our studies suggest that MG both produce and respond to factors that stimulate MG reprogramming and proliferation following retinal injury. The identification of a core set of regeneration-associated signaling pathways required for MG reprogramming not only furthers our understanding of retina regeneration in fish but also suggests targets for enhancing regeneration in mammals. : Müller glia are responsible for mediating retina regeneration in zebrafish. Wan et al. report on signaling systems activated by injury and necessary for retina regeneration. They identify a variety of growth factors and cytokines that stimulate Müller glia proliferation and retina regeneration by activating Mapk, Pi3k, β-catenin, and pStat3 signaling pathways. Their studies reveal a remarkable synergy and crosstalk among the growth factors and cytokines and provide evidence that this crosstalk is necessary for Müller glia proliferation.