Leptin and IL-6 Family Cytokines Synergize to Stimulate Müller Glia Reprogramming and Retina Regeneration

Abstract

Summary: Unlike mammals, zebrafish can regenerate a damaged retina. This remarkable regenerative response is mediated by Müller glia (MG) that undergo a reprogramming event that drives their proliferation and the generation of multipotent progenitors for retinal repair. The mechanisms that drive MG reprogramming are poorly understood. Here, we report that Leptin and Gp130-coupled receptors, acting via a Jak/Stat signaling pathway, stimulate MG reprogramming and progenitor formation in the injured retina. Importantly, we find that ascl1a gene expression, which drives MG reprogramming in fish and mammals, is regulated in a Jak/Stat-dependent manner and requires consensus Stat-binding sites for injury-dependent activation. Finally, we identify cytokines that are induced by retinal injury and exhibit a remarkable synergy in their ability to activate Jak/Stat signaling and MG reprogramming in the uninjured retina. Our study not only furthers our understanding of retina regeneration in zebrafish but also suggests new strategies for awakening retina regeneration in mammals. : In zebrafish, Müller glia respond to retinal injury by undergoing a reprogramming event that allows them to divide and generate progenitors for retinal repair. Zhao et al. now show that Jak/pStat3 signaling is necessary for progenitor formation. They report that pStat3 signaling is activated by cytokines expressed by injury-responsive Müller glia. They find that Leptin and IL-11 are induced in the injured retina, necessary for retina regeneration, and sufficient for stimulating Müller glia reprogramming in the uninjured retina.