Muller glia and neuronal regeneration in the retina

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DESCRIPTION (provided by applicant): The possibility of neural regeneration from glial cells has recently gained credibility and popularity. We have previously shown that large numbers of Muller glia in the postnatal chicken retina can re-enter the cell cycle, de-differentiate, express transcription factors normally expressed by retinal progenitors, and produce a few new neurons (Fischer and Reh, 2001 a). We found that Muller glia can become retinal progenitor-like cells in response to acute damage (Fischer and Reh, 2001 a) or in response to the combination of insulin and FGF2 (fibroblast growth factor 2) in the absence of damage (Fischer et al., 2002b). Thus, Muller glia hold the potential to act as a cellular source of neural regeneration within the retina. However, the mechanisms that regulate the ability of Muller glia to re-enter the cell cycle, become progenitor cells, and differentiate as neurons remain unknown and unexplored. The specific hypothesis that underlies this proposal is that MAP kinase, Jak/STAT and Notch signaling pathways regulate the different responses of Muller glia to retinal damage. Based on preliminary data we will test the following hypotheses. (1) MAP kinase pathways promote glial de-differentiation and proliferation, and suppress aspects of reactive gliosis such as GFAP (glial fibrillary acidic protein) expression. (2) CNTF (ciliary neurotrophic factor)/Jak-STAT signaling promotes glial maturation, promotes GFAP expression, and suppresses glial proliferation. (3) Notch-mediated signaling prevents neuronal differentiation from Muller glia-derived progenitors in acutely damaged retinas. (4) Mature, damaged retinas lack the cues required for neuronal differentiation of progenitor cells. This proposal provides specific aims and describes experiments to test the above-listed hypotheses. Data produced by these experiments will provide valuable information regarding the possibility that Muller glia can be used as a source of neural regeneration within the retina. In addition, the data will provide new insights into the secreted factors and signaling pathways that control gliosis and the ability of glial cells to re-enter the cell cycle. This information could be applied to not only stimulate neural regeneration to treat sight-threatening diseases of the retina, but also to control gliosis that may be detrimental to the pathogenesis of retinal disorders.