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Notch-Signaling in Retinal Regeneration and Müller Glial Plasticity

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Notch-Signaling in Retinal Regeneration and Müller glial Plasticity DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Kanika Ghai, MS Neuroscience Graduate Studies Program The Ohio State University 2009 Dissertation Committee: Dr. Andy J Fischer, Advisor Dr. Heithem El-Hodiri Dr. Susan Cole Dr. Paul Henion Copyright by Kanika Ghai 2009 ABSTRACT Eye diseases such as blindness, age-related macular degeneration (AMD), diabetic retinopathy and glaucoma are highly prevalent in the developed world, especially in a rapidly aging population. These sight-threatening diseases all involve the progressive loss of cells from the retina, the light-sensing neural tissue that lines the back of the eye. Thus, developing strategies to replace dying retinal cells or prolonging neuronal survival is essential to preserving sight. In this regard, cell-based therapies hold great potential as a treatment for retinal diseases. One strategy is to stimulate cells within the retina to produce new neurons. This dissertation elucidates the properties of the primary support cell in the chicken retina, known as the Müller glia, which have recently been shown to possess stem-cell like properties, with the potential to form new neurons in damaged retinas. However, the mechanisms that govern this stem-cell like ability are less well understood. In order to better understand these properties, we analyze the role of one of the key developmental processes, i.e., the Notch-Signaling Pathway in regulating proliferative, neuroprotective and regenerative properties of Müller glia and bestow them with this plasticity. The first part of this dissertation is a description of embryonic studies that verify the use of a pharmacological inhibitor of Notch-signaling, DAPT, as well as RNA interference molecules that block downstream effectors of Notch – Hes1 and Hes5. We find that inhibition of γ-secretase activity associated with Notch and ii silencing of the bHLH effectors Hes1 and Hes5 have distinctly different outcomes on cell-fate specification of cultured chicken retinal progenitors. Further, our studies reveal that Notch-signaling plays a limited but important role during retinal regeneration. Components of the Notch-signaling pathways are transiently upregulated in proliferating Müller glia after damage in a chicken retina and blocking Notch after damage enhances some neural regeneration from glial-derived progenitors. In the second part of this dissertation, we analyze the role of the Notch pathway in the postnatal retina in the absence of damage. We find that components of the Notch-signaling pathway are expressed at low levels in most Müller glia in undamaged retina. Further, Notch-signaling influences the phenotype and function of Müller glia in the mature retina; low levels of Notch-signaling diminish the neuroprotective capacity of Müller glia, but are required to maintain their ability to become progenitor-like cells. We also find that there is cross-talk between Notch and MAPK pathways – FGF2, a secreted protein that activates the MAPK pathway, also induces the expression of Notch pathway genes. Further, active Notch-signaling is required for the FGF2-mediated accumulation of p38 MAPK and pCREB in Müller glia. Our data indicate that Notch-signaling is down-stream of and is required for FGF2/MAPK- signaling to drive the proliferation of Müller glia. The third part of this dissertation describes the patterning of the immature zone of cells present at the retinal margin, called the circumferential marginal zone (CMZ). Our data indicates that there is a gradual spatial restriction of this zone of progenitor cells during late stages of embryonic development and that there are iii regional differences in the maturity of cells within the CMZ. Further, we find that retinal neurons adjacent to the CMZ in far peripheral regions of the temporal retina remain immature and differentiate far more slowly compared to the neurons in central regions of the retina and that the microenvironment at the periphery of the retina that promotes the persistence of a zone of retinal progenitors may also keep some types of neurons immature for extended periods of time. The last part of this dissertation describes the morphological and mechanistic properties of a unique subset of interneurons we discovered in the chicken retina, called the serotonin-accumulating bipolar cells. Even though serotonin is synthesized by amacrine cells, another type of interneuron present in the retina, it transiently accumulates in this distinct type of bipolar neuron. The accumulation of endogenous or exogenous serotonin by bipolar neurons is blocked by selective reuptake inhibitors. Further, inhibition of monoamine oxidase (A) prevents the degradation of serotonin in bipolar neurons, suggesting that MAO(A) is present in these neurons. Our data indicates that serotonin-accumulating bipolar neurons perform glial functions in the retina by actively transporting and degrading serotonin that is synthesized in neighboring amacrine cells. Taken together, the data presented in this dissertation furthers understanding of Müller glial plasticity. This information could be applied to stimulating neural regeneration, harnessing Müller glia as a localized source of stem cells intrinsic to the retina, developing pharmacological therapies targeted to the glia and countering neuronal death in sight-threatening diseases. Additionally, our studies on serotonin- accumulating bipolar cells have implications for understanding the mechanisms of iv melatonin biosynthesis and retinal circadian rhythms, dysfunctions of which lead to photoreceptor degeneration and loss of vision. \ v DEDICATION Dedicated to my dear grandfathers I.S. Chowdhary and R.L. Ghai vi ACKNOWLEDGEMENTS As I write this dissertation, I have several people to thank for supporting me through the long drawn-out ordeal that is the PhD. Undoubtedly on top of this list are my parents, brother, and grandparents who have always been my pillars of strength. I can’t thank them enough for keeping me emotionally grounded and for being my most ardent cheerleaders through this process. I am grateful to my mentor, Dr. Andy Fischer for helping me develop my professional skills and teaching me how to be a better scientist. Andy’s passion for science, coupled with his ability to multi-task experiments, grants/paper writing, family, administrative duties and yet, maintaining his great sense of humor and being there whenever I needed him is inspiring and mind-boggling. I couldn’t have asked for a better advisor through graduate school. Other important people I am grateful to: Dr. Georgia Bishop and Dr. Ning Quan for their indispensable support and advice over the years; the fantastic members of my Candidacy and Defense Committees including Dr. Heithem El-Hodiri, Dr. Paul Henion, Dr. Susan Cole and Dr. Dick Burry for their constructive criticism about my research projects; Dr. Vidita Vaidya at TIFR, Mumbai, who introduced me to the exciting world of neuroscience; the Professors at the Life Science Department, St. Xavier’s College, Mumbai especially Dr. Radiya-Pacha Gupta, Dr. Sujayakumari, Dr. vii Donde, Dr. D’Silva, Dr. Mangalore and my excellent Biology teacher in high school Ms. Vasanthy. My dear husband, Rajat, thank you for waiting patiently for me to finish, encouraging and pushing me, and enduring a long-distance marriage! A big thank you to all my friends who know what it’s like to be in graduate school, especially Sirsha, Bharath, Pushkar, Kavitha, Harini, Shwetank, Trupti and Arnaz – you were there when I needed you and I am grateful for that. I also want to acknowledge some colleagues and friends who have inspired me in little ways, including Khalid, Nupur, Greg, Sharmila, Richa, Cynthia, Kristen, Leah, Leena and Litty. It’s been such a pleasure working in a lab where doing science is a fun and creative learning process. Chris deserves special mention here – my dissertation would not have been possible without his excellent help with experiments and his enthusiasm to work tirelessly and on weekends. Many thanks to Jennifer for patiently walking me through lab techniques, sharing graduate school woes and all those scientific discussions. I would also like to acknowledge the support and friendship of other lab members including Eric, Melissa, Pat, Ami and Rachel. In the end, I am grateful that I was given the opportunity to be part of the Neuroscience Department at OSU. Columbus has been a welcoming home away from home for me and I shall cherish the memories associated with this University and the city for years to come. viii VITA 1980………………………………………...Mumbai, India 2001………………………………………...BS, Life Sciences, St. Xavier’s College, Mumbai 2003………………………………………..MS, Life Sciences, Mumbai University 2003 – 2009…………………………….......Graduate Research Associate Neuroscience Graduate Studies Program The Ohio State University PUBLICATIONS 1. Ghai K, Zelinka C, Fischer AJ. Serotonin released from amacrine neurons is scavenged and degraded in bipolar neurons in the retina. J. Neurochem. 2009 Oct; 111(1):1-14 2. Ghai K, Stanke JJ, Fischer AJ. Patterning of the circumferential marginal zone of progenitors in the chicken retina. Brain Res. 2008 Feb 4;1192:76-89 3. Fischer AJ, Stanke JJ, Ghai K, Scott M, Omar G. Development of bullwhip neurons in the embryonic chicken retina. J Comp Neurol. 2007 Aug 1;503(4):538-49. FIELDS OF STUDY Major Field: Neuroscience ix TABLE OF CONTENTS Abstract
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