Abstract
BackgroundEvidence emerging from a variety of approaches used in different species suggests that Müller cell function may extend beyond its role of maintaining retinal homeostasis to that of progenitors in the adult retina. Enriched Müller cells in vitro or those that re-enter cell cycle in response to neurotoxin-damage to retina in vivo display multipotential and self-renewing capacities, the cardinal features of stem cells.Methodology/Principal FindingsWe demonstrate that Notch and Wnt signaling activate Müller cells through their canonical pathways and that a rare subset of activated Müller cells differentiates along rod photoreceptor lineage in the outer nuclear layer. The differentiation of activated Müller cells along photoreceptor lineage is confirmed by multiple approaches that included Hoechst dye efflux analysis, genetic analysis using retina from Nrl-GFP mice, and lineage tracing using GS-GFP lentivirus in wild type and rd mice in vitro and S334ter rats in vivo. Examination of S334ter rats for head-neck tracking of visual stimuli, a behavioral measure of light perception, demonstrates a significant improvement in light perception in animals treated to activate Müller cells. The number of activated Müller cells with rod photoreceptor phenotype in treated animals correlates with the improvement in their light perception.Conclusion/SignificanceIn summary, our results provide a proof of principle for non-neurotoxin-mediated activation of Müller cells through Notch and Wnt signaling toward the regeneration of rod photoreceptors.
Highlights
Muller cells are the sole glia generated by retinal stem cells/ progenitors
As direct evidence of their neurogenic potential in vivo, we demonstrated that Muller cells, prospectively enriched as side population (SP) cells, integrated and generated lamina-specific retinal neurons after transplantation into mechanically injured retina [13]
The mechanism that activates these dormant Muller cells is likely to involve pathways that integrate both cell-intrinsic and cell-extrinsic pathways and evidence suggests that Notch and Wnt signaling plays an important role in this regard [13]
Summary
Muller cells are the sole glia generated by retinal stem cells/ progenitors. Similar to the temporal pattern of generation of glia elsewhere in the central nervous system (CNS), Muller cells are born during the late stages of retinal histogenesis when the majority of neuronal cell types are already in the process of generation [1]. Progenitors during late histogenesis face the decision either to differentiate into neurons or glia. The mechanism through which such a decision is made is not clear, but the emerging evidence points towards Notch signaling. Notch signaling plays an important role in the maintenance of stem cells/progenitors throughout retinal histogenesis [6,7], suggesting that it acquires a gliogenic role during Muller cell differentiation, presumably through the interactions with the JAK-STAT pathway [8,9,10]. Evidence emerging from a variety of approaches used in different species suggests that Muller cell function may extend beyond its role of maintaining retinal homeostasis to that of progenitors in the adult retina. Enriched Muller cells in vitro or those that re-enter cell cycle in response to neurotoxin-damage to retina in vivo display multipotential and self-renewing capacities, the cardinal features of stem cells
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