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Adam Phillip Oel Genetic regulation of photoreceptor specification in the tetrachromat zebrafish retina by Adam Phillip Oel A thesis submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Physiology, Cell, and Developmental Biology Department of Biological Sciences University of Alberta © Adam Phillip Oel, 2018 Abstract Vertebrate vision is mediated through the absorption of light by the rod and the cone photoreceptors. Early jawed vertebrates initially had four cone subtypes, which sampled different regions of the visual spectrum to allow colour vision, and a single rod type which enabled vision in dim light. Many lineages of vertebrates retain this original complement of photoreceptors, but genetic mechanisms of photoreceptor specification have been chiefly explored in mammals, which have lost two cone subtypes. Our understanding of the genetic regulation of photoreceptor diversity in the archetypical vertebrate eye, and how this regulation has evolved in different lineages, is therefore incomplete. I used the zebrafish, a diurnal vertebrate that produces the four original cone subtypes and one rod subtype, to investigate the genetic specification of photoreceptor diversity in tetrachromats, and to identify possible genetic mechanisms exploited by various vertebrate lineages to recalibrate their photoreceptor diversity in response to novel evolutionary pressures. The zebrafish UV cone is homologous to the mouse S cone, while the zebrafish blue cone has no mouse homolog. It was previously demonstrated that the T-box transcription factor gene tbx2b modulates UV cone and rod abundances in larval zebrafish, but regulators of tbx2b were unknown. Furthermore, regulation of the blue cone type was wholly unknown. On the basis of genetic interaction in early retinogenesis, my colleagues and I examined the genetic interaction of the BMP ligand gene gdf6a and tbx2b on larval photoreceptor diversity. We found that gdf6a modulates the actions of tbx2b in governing UV cone and rod abundance, and on its own modulates blue cone abundance. Together, this represents the beginning of the first genetic pathway regulating tetrachromat cone diversity, including of the ancient blue cones not found in mammalian retinas. Molecular evidence suggests that rod genes evolved out of pre-existing cone genes, and the current consensus is that rods probably evolved from cones. Previous work profiling the gene expression of developing mouse rods had suggested a transient cone signature. This led to the hypothesis that vertebrate rods routinely develop from cone- fated precursors. My colleagues and I tested this hypothesis by comparing mouse and ii zebrafish photoreceptor development. We found that a majority of mouse rods transiently but robustly expressed signature cone genes, but some small proportion of mouse rods did not. I found that zebrafish larvae did not have rods with cone gene expression history. In light of additional evidence that early mammals increased the abundance of rod photoreceptors for a nocturnal lifestyle, we proposed that mammals diverted normally highly abundant cone-destined cells to the rod phenotype. We further proposed that early mammals may have exploited regulatory or activity changes in the transcription factor Nrl as a mechanism. The body of mouse photoreceptor specification literature features Nrl as a central node in that transcription factor network, and it was not known whether nrl had conserved activity in zebrafish or any species beyond mouse or mammals. I therefore examined the role of nrl in zebrafish photoreceptor specification. I found nrl to be necessary and sufficient for the rod phenotype in larvae, indicating conservation of nrl function between fish and mammals. Unlike in mammals, I further found that nrl was not required for adult rod production. This is the first evidence for an nrl-independent rod developmental pathway. Finally, I tested the rod-inductive ability of a panel of nrl homologs from several vertebrate taxa, and found that even basally-branching vertebrates have an nrl homolog which can promote the rod phenotype. This suggests that a role for nrl in rod specification may be ancestral in vertebrates. Cumulatively, the work in this thesis identified the first genetic regulator of the tetrachromat blue cone, established a novel regulatory pathway governing UV cone and rod abundance, and identified a deep conservation in rod developmental genetics between mammals and zebrafish larvae. It also identified a possible novel rod developmental pathway, which may be a genetic mechanism by which other vertebrate lineages modulate photoreceptor diversity. Finally, it positioned zebrafish to serve as the basis for future direct comparisons of photoreceptor specification genetics between tetrachromats and mammals. iii Preface Two chapters in this PhD thesis have been previously published: Chapter 2 was published as: Michèle G. DuVal, A. Phillip Oel, and W. Ted Allison. 2014. “gdf6a Is Required for Cone Photoreceptor Subtype Differentiation and for the Actions of tbx2b in Determining Rod Versus Cone Photoreceptor Fate”. PloS One 9, e92991. All authors conceived, designed, and performed the experiments, and analyzed the data, and edited the manuscript. MGD and WTA wrote the manuscript. I was an equal contributor to 6 of the 9 major experiments, and to 6 of 12 total figure elements. Chapter 3 was published as: Jung-Woong Kim1, Hyun-Jin Yang1, A. Phillip Oel1, Matthew John Brooks, Li Jia, David Charles Plachetzki, Wei Li, W. Ted Allison2, and Anand Swaroop2. 2016. “Recruitment of Rod Photoreceptors from Short-Wavelength-Sensitive Cones during the Evolution of Nocturnal Vision in Mammals”. Developmental Cell 37, 520-532. 1Co-first authors; 2co-corresponding authors. JK: mouse experiments, data analysis, evolutionary analysis, next-gen sequencing analysis, original draft. HY: mouse experiments, data analysis, next-gen sequencing analysis, original draft. APO: data analysis, and zebrafish experiment conceptualization, performance, and analysis. MJB: next-gen sequencing experiments, data curation, and analysis, and evolutionary analysis. LJ: mouse resource generation. DCP: next-gen sequencing analysis, and phylogenetic analysis. WL: mouse resource generation. WTA: zebrafish experiment conceptualization, data analysis, supervision. AS: data analysis, supervision, project administrator. JK, HY, APO, MJB, DCP, WL, WTA, and AS reviewed and edited the manuscript. iv Acknowledgements This journey was only possible because of the enormous amount of support I received while undertaking it. I received this support from many sources over the years, but chiefly among them: I would like to gratefully honour my supervisor, Ted Allison, for taking a chance on me six years ago as I wandered out of my undergrad ago toward what I hoped was the right way to do science. Throughout this time, he has made room for me to learn, grow, disagree, and more frequently to initially disagree and then learn more and agree later. I have truly felt like a peer in the design and execution of the research I performed under his supervision. I thank him for his long-term confidence in me, for helping me to become a scientist, and for encouraging me to dream big. I thank the many and varied members of the Allison lab, with whom it has been a pleasure to work, and who have been another enormous source of support for me over the years. I especially wish to thank Michèle Duval, who has continually inspired me in every way, from work ethic, to service, wisdom and perspective. I thank my family and friends for their constant support and for providing a moment away from it all whenever I needed it. This includes my mother and sister Shelley and Sara Traves, and my second family Bonnie and Lester Shantz and Michelle Sims. Finally, I thank my partner Kailen Shantz for everything over the years. We have done our graduate programs in separate countries, but his love, support, and wisdom have always been immediate and invaluable. I could not have done this without him. v Table of Contents CHAPTER 1: ............................................................................................................................................................ 1 GENERAL INTRODUCTION ...................................................................................................................................... 1 1.1 ANATOMY AND DEVELOPMENT OF THE RETINA ...................................................................................................... 2 1.1.1 Structure and elements of the retina ..................................................................................................... 2 1.1.2 Function of the retinal components ....................................................................................................... 5 1.1.3 Function of the photoreceptors ............................................................................................................. 7 1.1.4 Rod/Cone differences in phototransduction ........................................................................................ 11 1.1.5 Retinal histogenesis ............................................................................................................................. 11 1.2 GENETIC CONTROL OF THE PRODUCTION OF PHOTORECEPTORS ............................................................................... 16 1.2.1 Specifying the photoreceptor lineage .................................................................................................
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