Mechanisms underlying Muller glia’s regenerative potential

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Summary Blinding eye diseases, like glaucoma, macular degeneration, and retinitis pigmentosa cause neuronal degeneration and lead to severe disability. The restoration of lost neurons using cell transplantation holds promise, but the degenerating retina may prove resistant to exogenous cell integration as it undergoes structural remodeling with disease progression. An alternative approach is to use endogenous stem cells for retinal neuron regeneration. Remarkably, in zebrafish, Müller glia can function as stem cells and regenerate retinal neurons lost to injury or disease. Although Müller glia are found in both the zebrafish and mammalian retina, and share structure and function; only in fish do they regenerate new neurons. Over the past decade, we have learned a lot about the genetic programs and signaling pathways that regulate Müller glia reprogramming and proliferation in zebrafish; however, we still lack an understanding of why they can mount a regenerative response in fish, but not in mammals. It seems likely this information resides in Müller glia’s quiescent state. Interestingly, Notch signaling has recently emerged as an important difference between pro- regenerative Müller glia in the zebrafish retina and non-regenerative Müller glia in the mammalian retina. In zebrafish Müller glia, Notch signaling is active in the basal state and must be suppressed for regeneration to ensue; however, in mice Notch signaling is essentially absent from Müller glia beyond postnatal stages. Interestingly, Notch signaling is also associated with radial glial stem cells in the brain and its suppression is necessary for their cell division and neuronal regeneration. Furthermore, Notch signaling can amplify stochastic events by lateral inhibition and thereby, may drive Müller cell heterogeneity. Zebrafish Müller glia heterogeneity is suggested by differences in gene expression, spontaneous proliferation, and response to retinal injury. In this grant we propose to further characterize Müller glia cell heterogeneity in the uninjured zebrafish retina and connect this heterogeneity to Müller glia’s regenerative potential. In addition, we will investigate how Notch signaling impacts the Müller glia transcriptome to regulate its regenerative properties. It is anticipated that these studies will provide new insights into retina regeneration in zebrafish and lead to new strategies for stimulating Müller glia’s regenerative response in mammals.