Doctor of Philosophy, The Ohio State University, 2017, Neuroscience Graduate Studies Program

Eye diseases that result in blindness are often caused by the death of retinal neurons. Muller glia are the major glial support cells in the retina and possess the potential to reprogram into neurogenic progenitor cells. In the fish, Muller glia are able to regenerate a fully functional retina following severe retinal damage. In avian and mammalian retinas, Muller glia retain their regenerative potential but to an insufficient extent to restore lost vision. A better understanding of the mechanisms that govern the reprogramming of Muller glia into neurogenic Muller glia-derived progenitor cells (MGPCs) may allow us to harness these cells in a therapeutically useful context. This dissertation examines the cell signaling mechanisms that regulate Muller glia homeostasis, de-differentiation, proliferation, and neurogenesis. The first chapter focuses on how Hedgehog signaling stimulates Muller glia to reprogram into proliferating progenitors in the chick retina. We show that the Hedgehog-pathway components are up-regulated in damaged retinas when MGPCs are known to form. Furthermore, we find that the Shh-ligand is potentially released by retinal ganglion cells and received by proliferating Muller glia. We report that activation of the Hedgehog pathway increases Muller glia proliferation in damaged and FGF2-stimulated retinas. Consistent with these findings, inhibition of Hedgehog-signaling at the level of the ligand, receptor, and transcription factors attenuate MGPC formation. Activation of Hedgehog signaling in the absence of damage or FGF2-application has no effect on Muller glia. We propose a model wherein retinal damage or FGF2-stimulation renders Muller glia responsive to the mitogenic effects of Hedgehog-signaling. The second chapter examines how Jak/Stat signaling impacts the regenerative capacity of the avian retina. We find that Jak/Stat signaling is rapidly activated in Muller glia in response to retinal damage. We also show that inhibition of the Jak/Sta (open full item for complete abstract)

Committee: Andrew Fischer PhD (Advisor); Dana McTigue PhD (Committee Member); Heithem El-Hodiri PhD (Committee Member); Karl Obreitan PhD (Committee Member) Subjects: Neurosciences