Nelson, C.M., Ackerman, K.M., O'Hayer, P., Bailey, T.J., Gorsuch, R.A., and Hyde, D.R. (2013) Tumor Necrosis Factor-Alpha Is Produced by Dying Retinal Neurons and Is Required for Muller Glia Proliferation during Zebrafish Retinal Regeneration. The Journal of neuroscience : the official journal of the Society for Neuroscience. 33(15):6524-6539.
Intense light exposure causes photoreceptor apoptosis in dark-adapted adult albino zebrafish (Danio rerio). Subsequently, Müller glia increase expression of the Achaete-scute complex-like 1a (Ascl1a) and Signal transducer and activator
of transcription 3 (Stat3) transcription factors and re-enter the cell cycle to yield undifferentiated neuronal progenitors
that continue to proliferate, migrate to the outer nuclear layer, and differentiate into photoreceptors. A proteomic analysis
of light-damaged retinal homogenates, which induced Müller glia proliferation when injected into an undamaged eye, revealed
increased expression of tumor necrosis factor α (TNFα) signaling proteins relative to undamaged retinal homogenates. TNFα
expression initially increased in apoptotic photoreceptors and later in Müller glia. Morpholino-mediated knockdown of TNFα
expression before light damage diminished the expression of both Ascl1a and Stat3 in Müller glia and significantly reduced
the number of proliferating Müller glia without affecting photoreceptor cell death. Knockdown of TNFα expression in the Müller
glia resulted in fewer proliferating Müller glia, suggesting that Müller glial-derived TNFα recruited additional Müller glia
to re-enter the cell cycle. While TNFα is required for increased Ascl1a and Stat3 expression, Ascl1a and Stat3 are both necessary
for TNFα expression in Müller glia. Apoptotic inner retinal neurons, resulting from intravitreal injection of ouabain, also
exhibited increased TNFα expression that was required for Müller glia proliferation. Thus, TNFα is the first molecule identified
that is produced by dying retinal neurons and is necessary to induce Müller glia to proliferate in the zebrafish retinal regeneration
response.