title: Leptin and IL-6 family cytokines synergize to stimulate Müller glia reprogramming and retina regeneration.
abstract: 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.
authors.affiliation: Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Zhao
authors.affiliation: Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Wan
authors.affiliation: Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Curtis
authors.initials: C
authors.lastname: Powell
authors.affiliation: Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Ramachandran
authors.affiliation: Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Martin G
authors.initials: MG
authors.lastname: Myers
authors.affiliation: Molecular and Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: neuroman@umich.edu.
authors.forename: Daniel
authors.initials: D
authors.lastname: Goldman
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D065150:Cellular Reprogramming / Q000502:physiology*; D029721:Drosophila Proteins / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism*; D053612:Janus Kinases / Q000378:metabolism; D020738:Leptin / Q000378:metabolism*; D009416:Nerve Regeneration / Q000502:physiology*; D058953:Neural Stem Cells / Q000378:metabolism; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D012160:Retina / Q000293:injuries / Q000378:metabolism / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; D015850:Interleukin-6; D020738:Leptin; D050796:STAT3 Transcription Factor; D014157:Transcription Factors; D029961:Zebrafish Proteins; C494089:stat3 protein, zebrafish; D053612:Janus Kinases; C085845:hop protein, Drosophila