title: Repressing notch signaling and expressing TNFα are sufficient to mimic retinal regeneration by inducing Müller glial proliferation to generate committed progenitor cells.
abstract: Retinal damage in teleosts, unlike mammals, induces robust Müller glia-mediated regeneration of lost neurons. We examined whether Notch signaling regulates Müller glia proliferation in the adult zebrafish retina and demonstrated that Notch signaling maintains Müller glia in a quiescent state in the undamaged retina. Repressing Notch signaling, through injection of the γ-secretase inhibitor RO4929097, stimulates a subset of Müller glia to reenter the cell cycle without retinal damage. This RO4929097-induced Müller glia proliferation is mediated by repressing Notch signaling because inducible expression of the Notch Intracellular Domain (NICD) can reverse the effect. This RO4929097-induced proliferation requires Ascl1a expression and Jak1-mediated Stat3 phosphorylation/activation, analogous to the light-damaged retina. Moreover, coinjecting RO4929097 and TNFα, a previously identified damage signal, induced the majority of Müller glia to reenter the cell cycle and produced proliferating neuronal progenitor cells that committed to a neuronal lineage in the undamaged retina. This demonstrates that repressing Notch signaling and activating TNFα signaling are sufficient to induce Müller glia proliferation that generates neuronal progenitor cells that differentiate into retinal neurons, mimicking the responses observed in the regenerating retina.
authors.affiliation: Department of Biological Sciences and the Center for Zebrafish Research, Galvin Life Sciences Building, University of Notre Dame, Notre Dame, Indiana 46556.
authors.forename: Clay
authors.initials: C
authors.lastname: Conner
authors.affiliation: Department of Biological Sciences and the Center for Zebrafish Research, Galvin Life Sciences Building, University of Notre Dame, Notre Dame, Indiana 46556.
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Ackerman
authors.affiliation: Department of Biological Sciences and the Center for Zebrafish Research, Galvin Life Sciences Building, University of Notre Dame, Notre Dame, Indiana 46556.
authors.forename: Manuela
authors.initials: M
authors.lastname: Lahne
authors.affiliation: Department of Biological Sciences and the Center for Zebrafish Research, Galvin Life Sciences Building, University of Notre Dame, Notre Dame, Indiana 46556.
authors.forename: Joshua S
authors.initials: JS
authors.lastname: Hobgood
authors.affiliation: Department of Biological Sciences and the Center for Zebrafish Research, Galvin Life Sciences Building, University of Notre Dame, Notre Dame, Indiana 46556 dhyde@nd.edu.
authors.forename: David R
authors.initials: DR
authors.lastname: Hyde
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology*; D063928:Ependymoglial Cells / Q000187:drug effects / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation; D008297:Male; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology*; D058953:Neural Stem Cells / Q000187:drug effects / Q000502:physiology*; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology; D009457:Neuroglia / Q000187:drug effects / Q000502:physiology; D051880:Receptors, Notch / Q000502:physiology*; D055351:Retinal Neurons / Q000187:drug effects / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000494:pharmacology; D015027:Zebrafish
chemical_list: D051880:Receptors, Notch; D014409:Tumor Necrosis Factor-alpha
keywords: Ascl1; Müller glia; Notch signaling; Stat3; quiescence; retinal regeneration