Nestin Regulates Muller Glia Proliferation After Retinal Injury

PURPOSE. The proliferative and neurogenic potential of retinal Muller glia after injury varies widely across species. To identify the endogenous mechanisms regulating the proliferative response of mammalian Muller glia, we comparatively analyzed the expression and function of nestin, an intermediate filament protein established as a neural stem cell marker, in the mouse and rat retinas after injury. METHODS. Nestin expression in the retinas of C57BL/6 mice and Wistar rats after methyl methanesulfonate (MMS)-induced photoreceptor injury was examined by immunofluorescence and Western blotting. Adeno-associated virus (AAV)-delivered control and nestin short hairpin RNA (shRNA) were intravitreally injected to rats and Muller glia proliferation after MMS-induced injury was analyzed by BrdU incorporation and immunofluorescence. Photoreceptor removal and microglia/macrophage infiltration were also analyzed by immunofluorescence. RESULTS. Rat Muller glia re-entered the cell cycle and robustly upregulated nestin after injury whereas Muller glia proliferation and nestin upregulation were not observed in mice. In vivo knockdown of nestin in the rat retinas inhibited Muller glia proliferation while transiently stimulating microglia/macrophage infiltration and phagocytic removal of dead photoreceptors. CONCLUSIONS. Our findings suggest a critical role for nestin in the regulation of Muller glia proliferation after retinal injury and highlight the importance of cross species analysis to identify the molecular mechanisms regulating the injury responses of the mammalian retina.

Automated summary

The proliferative and neurogenic potential of retinal Muller glia after injury varies widely across species. This study reveals that nestin plays a critical role in regulating the proliferative response of rat Muller glia after retinal injury, while this response is not observed in mice. The findings highlight the importance of cross species analysis to understand the molecular mechanisms of injury response in the mammalian retina.