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C. M. Nelson, R. A. Gorsuch, D. R. Hyde; Identification of Müller Glia Proliferation Signaling Pathways. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2662.
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Intense light exposure causes photoreceptor apoptosis in dark-adapted adult zebrafish. After 16 hours of light-treatment, maximal cell death is observed, followed by Müller glia reentering the cell cycle to yield transiently amplifying pluripotent neuronal progenitor cells that migrate to the ONL and differentiate into photoreceptors. The signals that mediate the initiation of Müller glia proliferation remain unknown. We hypothesize that the dying photoreceptors generate a trans-acting signaling molecule that induces the regeneration response. This analysis attempts to identify the photoreceptor-generated signal that is required for regeneration.
To determine if dying photoreceptors produce a proliferation signal, adult albino zebrafish were either undamaged or light-damaged for 16 hours, their retinas were homogenized and the lysate was injected into healthy eyes. Lysate-injected eyes were subsequently harvested for immunohistochemical analysis of PCNA, which labels dividing cells. Undamaged and light-damaged protein lysates were analyzed by 2D gel electrophoresis and MALDI-TOF mass spectrometry to identify candidate signal proteins. These candidate proteins were immunolocalized in light-damaged retinas to determine their spatial and temporal expression patterns during photoreceptor apoptosis and regeneration. Inhibiting candidate protein expression revealed the role of these signaling pathways in initiating the Müller glia regeneration response.
Injection of light-damaged retinal lysates significantly increased the number of dividing Müller glia relative to control lysate-injected eyes. Proteomic techniques identified increased expression of specific signaling pathway proteins in the light-damaged lysate, which suggests they are the signals that induce Müller glia proliferation.
A trans-acting signal is generated by dying photoreceptors that stimulates Müller glia proliferation. Proteins from distinct candidate signaling pathways were identified that increase in expression in dying photoreceptors, which may induce Müller glial-derived photoreceptor regeneration.
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