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Dual Functions for Insulinoma-Associated 1 in Retinal Development

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Dual Functions for Insulinoma-Associated 1 in Retinal Development University of Kentucky UKnowledge Theses and Dissertations--Biology Biology 2015 DUAL FUNCTIONS FOR INSULINOMA-ASSOCIATED 1 IN RETINAL DEVELOPMENT Marie A. Forbes-Osborne University of Kentucky, [email protected] Right click to open a feedback form in a new tab to let us know how this document benefits ou.y Recommended Citation Forbes-Osborne, Marie A., "DUAL FUNCTIONS FOR INSULINOMA-ASSOCIATED 1 IN RETINAL DEVELOPMENT" (2015). Theses and Dissertations--Biology. 31. https://uknowledge.uky.edu/biology_etds/31 This Doctoral Dissertation is brought to you for free and open access by the Biology at UKnowledge. It has been accepted for inclusion in Theses and Dissertations--Biology by an authorized administrator of UKnowledge. For more information, please contact [email protected]. STUDENT AGREEMENT: I represent that my thesis or dissertation and abstract are my original work. Proper attribution has been given to all outside sources. I understand that I am solely responsible for obtaining any needed copyright permissions. I have obtained needed written permission statement(s) from the owner(s) of each third-party copyrighted matter to be included in my work, allowing electronic distribution (if such use is not permitted by the fair use doctrine) which will be submitted to UKnowledge as Additional File. I hereby grant to The University of Kentucky and its agents the irrevocable, non-exclusive, and royalty-free license to archive and make accessible my work in whole or in part in all forms of media, now or hereafter known. I agree that the document mentioned above may be made available immediately for worldwide access unless an embargo applies. I retain all other ownership rights to the copyright of my work. I also retain the right to use in future works (such as articles or books) all or part of my work. I understand that I am free to register the copyright to my work. REVIEW, APPROVAL AND ACCEPTANCE The document mentioned above has been reviewed and accepted by the student’s advisor, on behalf of the advisory committee, and by the Director of Graduate Studies (DGS), on behalf of the program; we verify that this is the final, approved version of the student’s thesis including all changes required by the advisory committee. The undersigned agree to abide by the statements above. Marie A. Forbes-Osborne, Student Dr. Ann C. Morris, Major Professor Dr. David F. Westneat, Director of Graduate Studies DUAL FUNCTIONS FOR INSULINOMA-ASSOCIATED 1 IN RETINAL DEVELOPMENT __________________________ DISSERTATION __________________________ A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the College of Arts and Sciences at the University of Kentucky By Marie A. Forbes-Osborne Lexington, Kentucky Director: Ann C. Morris, Associate Professor of Biology Lexington, Kentucky 2015 Copyright © Marie A. Forbes-Osborne 2015 ABSTRACT OF DISSERTATION DUAL FUNCTIONS FOR INSULINOMA-ASSOCIATED 1 IN RETINAL DEVELOPMENT Proper visual system function requires tightly controlled proliferation of a pool of relatively homogeneous retinal progenitor cells, followed by the stepwise specification and differentiation of multiple distinct cell types. These retinal cells, both neuronal and glial, must be generated in the correct numbers, and the correct laminar location to permit the formation of synaptic connections between individual cell types. After synapses are made, constant signaling is required as part of normal retinal function, and to maintain cellular identity and connectivity. These processes rely on both extrinsic and intrinsic signaling, with regulation of gene expression by cascades of transcription factors having a key role. While considerable work has been done to identify key regulators of retinal development, maturation, and homeostasis, many factors remain unidentified or poorly characterized, either at large or within the retina. One such factor is Insulinoma-associated 1 (Insm1). Known to function in endocrine cell, sympathetic and monoaminergic neuron, and olfactory epithelial cell differentiation and maturation, Insm1 is also a regulator of cell cycle progression in the adrenal system and cerebral cortex. Although Insm1 was previously considered a transcriptional regulator, recently, non- nuclear functions have also been identified. However, the retinal function of Insm1 remained a mystery. To determine the role of Insm1 in retinal development, I characterized the retinal expression pattern of Insm1, as well as the effect of perturbation of Insm1 expression levels at both the cellular and molecular level. Chapter 1 of this dissertation provides an overview of the retina and its development, vision and retinal degenerative diseases, and a review of Insm1 expression and function in tissues outside the retina. Chapter 2 presents data generated from the knockdown of the retinal-expressed zebrafish co-ortholog of Insm1, insm1a, which demonstrated a requirement for insm1a in proper differentiation of photoreceptor cells. Additionally, these experiments showed a cell cycle regulatory function for insm1a in retinal development. Characterization of a zebrafish insm1a mutant and functional examination of insm1a truncation variants is discussed in Chapter 3. Chapter 4 presents data from an RNA-Seq analysis of wild-type and Insm1 knockout mouse retinas at two developmental time points, and details transcriptional changes during retinal development in the absence of Insm1. Finally, Chapter 5 discusses the conclusions from the data generated for this dissertation, additional studies identified as the result of this work, and the implications of these results on our understanding of retinal development. KEYWORDS: Retina, Photoreceptor, Insm1, Development, Zebrafish, Mouse Marie A. Forbes-Osborne Student’s Signature December 10, 2015 Date DUAL FUNCTIONS FOR INSULINOMA-ASSOCIATED 1 IN RETINAL DEVELOPMENT By Marie A. Forbes-Osborne Ann C. Morris Director of Dissertation David F. Westneat Director of Graduate Studies December 10, 2015 Date For MB Really, Really. ACKOWLEDGEMENTS “Hard work spotlights the character of people: some turn up their sleeves, some turn up their noses, and some don't turn up at all.” –Sam Ewing Throughout life (and especially during graduate school) this quote has inspired me, and I have committed to always being the type person who turns up their sleeves. However, hard work seldom occurs in a vacuum, and good company can make difficult tasks far easier. Though this dissertation bears only my name, it is built on the hard work and knowledge of innumerable others. First, I owe more than I can ever express to my mother, Antoinette Forbes. She taught me the value of hard work and dedication from childhood. She made me a voracious learner, and more importantly, a limitless questioner. She never stifled my curiosity and showed me the value and importance of questions without answers. For this and so much more, I am forever grateful. Second, I would like to thank my doctoral advisor, Dr. Ann Morris. Far beyond simply giving knowledge, Ann gave me a toolbox to solve nearly any problem that presented itself. She also gave me the freedom to explore, experiment and make (not mention learn from) mistakes, all while being ready to swoop in and save the day if I couldn’t figure it out on my own. This made me a better scientist, and gave me the opportunity to learn to be independent, without fear of failing. She also showed me that excellent science must be accompanied by excellent writing and engaging presentation skills. Her continued support has been essential to my growth and success in the lab and in life. I would also like to express my gratitude to the members of my committee. Dr. Pete Mirabito, who offered me unbelievable support and guidance from the lab to the classroom. His emphasis on understanding why and how have forever changed the way that I look at and solve problems. Dr. Randal Voss, whose questions and observations often forced me outside my comfort zone. Without a doubt, this made me a more thorough researcher and a better student of science and the world. Dr. Liz Debski, who always held me to exceptionally high standards, and showed me the importance in being certain of the underlying facts and the best ways to present them. Lastly, Dr. Jayakrishna Ambati, who helped me understand the importance of making research work for the betterment of society, and the value of using basic science and simple techniques to answer real world difficult questions. Their assistance has been invaluable to me throughout. My initial research experiences came from Dr. Rebecca Kellum. Without her support and assistance I would never have found the passion for research. I will be forever grateful to her for all that she has done for me. Day to day, I have been fortunate to have amazing lab mates and department colleagues, who made the daily grind more enjoyable. Dr. Lakshmi Pillai-Kastoori, my batch- mate and confidant. I am forever thankful for her support and friendship. Wen Wen, who attacks every obstacle with unending enthusiasm. Every task is possible when untaken so positively. Stephen Wilson, who showed me the value of taking every opportunity to enjoy the high points, while never letting the low points destroy you. Cagney (CC) Coomer, who has brought a new vibrancy to the lab in the last year, and has reminded me how important it is to pass on what we have learned. Sara Perkins, our fabulous technician, who kept things together for all of us. Whether supporting us at the bench or keeping us in line, none of this work would be possible without her. She has also become one of my best friends during this time, and has made my life better in more ways than I can ever express. Michelle Geidt, who has been a great friend, always ready to shore up flagging energy any way possible. Melissa Keinath and Stephanie Bryant for a listening ear and copious help when the science got ahead of my abilities. Thank you all.
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