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The Signaling Pathways that Regulate the Proliferative and Neurogenic Capacity of Muller glia

Todd, Levi, Todd
http://rave.ohiolink.edu/etdc/view?acc_num=osu1510240057079338

Abstract Details

2017, Doctor of Philosophy, Ohio State University, 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/Stat pathway at the level of the gp130-receptor, Jak2 kinase, and Stat3 transcription factor each diminish the ability of Muller glia to reprogram in to proliferating progenitors. Importantly, we find that inhibition of Jak/Stat signaling increases the neurogenic capacity of MGPCs after damage. This chapter implicates Jak/Stat signaling as a key component of MGPC-mediated retinal regeneration and an attractive target for boosting the neurogenic potential of Muller glia. The third chapter analyzes how Retinoic acid (RA)-signaling regulates the proliferative and neurogenic potential of avian Muller glia. We find that the RA-component CRABP is specifically up-regulated by Muller glia in response to retinal injury. We also show that RA-activation increases MGPC formation in damaged and FGF2-treated retinas. This chapter also provides novel data that RA-activation can increase neural differentiation from MGPC progeny. Taken together, these data implicate RA-signaling has an important pathway in the regulation of Muller glia-mediated retinal regeneration. Collectively, the work described in this dissertation represents significant advances in understanding the mechanisms underlying retinal regeneration in the avian retina. Each chapter describes novel data regarding the signaling pathways that regulate the de-differentiation, proliferation, and neural differentiation of MGPCs. This work provides rationale for novel lines of inquiry into stimulating Muller glia-mediated regeneration in the mammalian retina.
Andrew Fischer, PhD (Advisor)
Dana McTigue, PhD (Committee Member)
Heithem El-Hodiri, PhD (Committee Member)
Karl Obreitan, PhD (Committee Member)
175 p.
Neurosciences
Muller glia; Eye diseases; Proliferative and Neurogenic Capacity

Recommended Citations

Citations

  • Todd, Todd, L. (2017). The Signaling Pathways that Regulate the Proliferative and Neurogenic Capacity of Muller glia [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1510240057079338

    APA Style (7th edition)

  • Todd, Todd, Levi. The Signaling Pathways that Regulate the Proliferative and Neurogenic Capacity of Muller glia. 2017. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1510240057079338.

    MLA Style (8th edition)

  • Todd, Todd, Levi. "The Signaling Pathways that Regulate the Proliferative and Neurogenic Capacity of Muller glia." Doctoral dissertation, Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1510240057079338

    Chicago Manual of Style (17th edition)

osu1510240057079338
362
© 2017, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.