Muller glia: roles in retinal homeostasis and neuronal regeneration

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Project Summary: There is a rapidly growing body of evidence that Müller glia can are a source of retinal progenitors to promote neural regeneration. Many studies have demonstrated that Müller glia can become proliferating progenitor cells in the retinas of different vertebrate species. Most reports have studied Müller glia-derived progenitors in acutely damaged retinas. However, little is known about the mechanisms that stimulate neurogenesis from Müller glia-derived progenitors in undamaged retinas or retinas undergoing slow, progressive degeneration. Furthermore, the regeneration of retinal neurons in warm-blooded vertebrates is limited compared to that seen in cold-blooded vertebrates. Therefore, the identification of the secreted factors and signaling pathways that permit and/or stimulate neural regeneration from Müller glia-derived progenitors is crucially important to developing new therapies to treat degenerative diseases of the human retina. We have obtained compelling novel preliminary data indicating that cell-signaling through the nuclear factor kappa-light- chain-enhancer of activated B cells (NFκB) and the activity of Enhancer of Zeste Homolog 2 (EZH2) impacts the de-differentation and reprogramming of Müller glia into proliferating, neurogenic retinal progenitors. We will investigate how the phenotype and plasticity of the Müller glia are regulated by NFκB and EZH2 in normal, damaged and growth factor-treated retinas. We will use a combination of pharmacological and genetic approaches to selectively activate or inhibit NFκB and EZH2 in Müller glia. We will compare and contrast how NFκB-signaling and EZH2-acitvity impact the formation of Müller glia-derived progenitors in chick and rodent model systems with different inherent capacities for retinal regeneration. We expect that the completion of the experiments described in this proposal will provide significant new information regarding how NFκB and EZH2 influence mature Müller glia, the formation of Müller glia-derived progenitors and regeneration of retinal neurons. Identification and understanding of the mechanisms that enhance the neurogenic potential of Müller glia is required to develop new therapies for sight-threatening diseases, such as glaucoma and macular degeneration that involve the loss of retinal neurons.