There is a rapidly growing body of evidence that Muller glia are a source of retinal progenitors to mediate neural regeneration. Many studies have demonstrated that Muller glia can become proliferating progenitor cells in the retinas of different vertebrate species. Nearly all reports have studied Muller glia-derived progenitors in acutely damaged retinas. However, little is known about the mechanisms that stimulate neurogenesis from Muller 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 Muller glia-derived progenitors is crucially important to developing new therapies to treat degenerative diseases of the human retina. We have obtained preliminary data indicating that signaling through the glucocorticoid receptor (GCR), p38 MAPK and signals derived from other types of retinal glia significantly impact the neurogenic potential of Muller glia. We will investigate the coordinated activity of different types of retinal glia including the Muller glia, microglia and the recently described Non-astrocytic Inner Retinal Glia-like (NIRG) cells. We have identified the NIRG cells as a distinct type of glial cell that is present in retina of birds, canines and primates. We believe that the NIRG cells influence the ability of Muller glia to become retinal progenitors. We expect that the completion of the experiments described in this proposal will provide significant new information regarding different signaling pathways, secreted factors, and how the microglia and NIRG cells influence the formation of Muller glia-derived retinal progenitors. Identification and understanding of the mechanisms that enhance the neurogenic potential of Muller glia is required to develop new therapies for sight-threatening diseases, such as glaucoma and macular degeneration that involve the loss of retinal neurons.

Public Health Relevance

A thorough understanding of the mechanisms that regulate the functions of glial cells is crucially important to the development of new therapies to treat sight-threatening diseases of the retina. Retinal Muller glia is known to have the potential to become neurogenic progenitor cells. Identification and understanding the mechanisms that regulate the neurogenic potential of Muller glia-derived progenitors is key to developing neuron-replacement therapies for the retina. This proposal seeks to identify important glial interactions and signaling pathways that enhance the ability of Muller glia to become proliferating progenitors and produce new functional neurons. A goal of this project is to study defined molecular mechanisms and signaling pathways that regulate glial functions related to reactivity, proliferation, and neuronal regeneration. The findings produced by the proposed studies will provide valuable new insights into the factors and signaling mechanisms that regulate inter-glial communication and glia- mediated neuronal regeneration.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Greenwell, Thomas
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Ohio State University
Schools of Medicine
United States
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Todd, Levi; Suarez, Lilianna; Quinn, Colin et al. (2018) Retinoic Acid-Signaling Regulates the Proliferative and Neurogenic Capacity of Müller Glia-Derived Progenitor Cells in the Avian Retina. Stem Cells 36:392-405
Wisely, C Ellis; Sayed, Javed A; Tamez, Heather et al. (2017) The chick eye in vision research: An excellent model for the study of ocular disease. Prog Retin Eye Res 61:72-97
Todd, Levi; Palazzo, Isabella; Squires, Natalie et al. (2017) BMP- and TGF?-signaling regulate the formation of Müller glia-derived progenitor cells in the avian retina. Glia 65:1640-1655
Todd, Levi; Squires, Natalie; Suarez, Lilianna et al. (2016) Jak/Stat signaling regulates the proliferation and neurogenic potential of Müller glia-derived progenitor cells in the avian retina. Sci Rep 6:35703
Zelinka, Christopher P; Volkov, Leo; Goodman, Zachary A et al. (2016) mTor signaling is required for the formation of proliferating Müller glia-derived progenitor cells in the chick retina. Development 143:1859-73
Todd, Levi; Suarez, Lilianna; Squires, Natalie et al. (2016) Comparative analysis of glucagonergic cells, glia, and the circumferential marginal zone in the reptilian retina. J Comp Neurol 524:74-89
Gallina, Donika; Palazzo, Isabella; Steffenson, Lillia et al. (2016) Wnt/?-catenin-signaling and the formation of Müller glia-derived progenitors in the chick retina. Dev Neurobiol 76:983-1002
Todd, Levi; Fischer, Andy J (2015) Hedgehog signaling stimulates the formation of proliferating Müller glia-derived progenitor cells in the chick retina. Development 142:2610-22
Fischer, Andy J; Zelinka, Christopher; Milani-Nejad, Nima (2015) Reactive retinal microglia, neuronal survival, and the formation of retinal folds and detachments. Glia 63:313-27
Gallina, Donika; Zelinka, Christopher Paul; Cebulla, Colleen M et al. (2015) Activation of glucocorticoid receptors in Müller glia is protective to retinal neurons and suppresses microglial reactivity. Exp Neurol 273:114-25

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