Tumor Necrosis Factor-Alpha Is Produced by Dying Retinal Neurons and Is Required for Müller Glia Proliferation during Zebrafish Retinal Regeneration

摘要: Intense light exposure causes photoreceptor apoptosis in dark-adapted adult albino zebrafish (Danio rerio). Subsequently, Muller glia increase expression of the Achaete-scute complex-like 1a (Ascl1a) and Signal transducer activator transcription 3 (Stat3) factors re-enter cell cycle to yield undifferentiated neuronal progenitors that continue proliferate, migrate outer nuclear layer, differentiate into photoreceptors. A proteomic analysis light-damaged retinal homogenates, which induced proliferation when injected an undamaged eye, revealed increased tumor necrosis factor α (TNFα) signaling proteins relative homogenates. TNFα initially apoptotic photoreceptors later glia. Morpholino-mediated knockdown before damage diminished both Ascl1a Stat3 significantly reduced number proliferating without affecting death. Knockdown resulted fewer glia, suggesting glial-derived recruited additional cycle. While is required for expression, are necessary Apoptotic inner neurons, resulting from intravitreal injection ouabain, also exhibited was proliferation. Thus, first molecule identified produced by dying neurons induce proliferate regeneration response.