Repressing notch signaling and expressing TNFα are sufficient to mimic retinal regeneration by inducing Müller glial proliferation to generate committed progenitor cells

• Published in: The Journal of neuroscience 2014-10, Vol.34 (43), p.14403-14419
• Main Authors: Conner, Clay, Ackerman, Kristin M, Lahne, Manuela, Hobgood, Joshua S, Hyde, David R
• Format: Article
• Language: English
• Subjects: Animals; Animals, Genetically Modified; Cell Proliferation - drug effects; Cell Proliferation - physiology; Danio rerio; Ependymoglial Cells - drug effects; Ependymoglial Cells - physiology; Female; Gene Expression Regulation; Male; Nerve Regeneration - drug effects; Nerve Regeneration - physiology; Neural Stem Cells - drug effects; Neural Stem Cells - physiology; Neurogenesis - drug effects; Neurogenesis - physiology; Neuroglia - drug effects; Neuroglia - physiology; Receptors, Notch - physiology; Retinal Neurons - drug effects; Retinal Neurons - physiology; Teleostei; Tumor Necrosis Factor-alpha - biosynthesis; Tumor Necrosis Factor-alpha - pharmacology; Zebrafish
• ISSN: 0270-6474; 1529-2401
• DOI: 10.1523/JNEUROSCI.0498-14.2014

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.