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A Focus on the Kisspeptin Receptor, Kiss1r Western University Scholarship@Western Electronic Thesis and Dissertation Repository 12-1-2014 12:00 AM Pathway-Specific Signaling and its Impact on erF tility: A Focus on the Kisspeptin Receptor, Kiss1r Maryse R. Ahow The University of Western Ontario Supervisor Dr. Andy Babwah The University of Western Ontario Graduate Program in Physiology A thesis submitted in partial fulfillment of the equirr ements for the degree in Doctor of Philosophy © Maryse R. Ahow 2014 Follow this and additional works at: https://ir.lib.uwo.ca/etd Part of the Molecular and Cellular Neuroscience Commons Recommended Citation Ahow, Maryse R., "Pathway-Specific Signaling and its Impact on erF tility: A Focus on the Kisspeptin Receptor, Kiss1r" (2014). Electronic Thesis and Dissertation Repository. 2537. https://ir.lib.uwo.ca/etd/2537 This Dissertation/Thesis is brought to you for free and open access by Scholarship@Western. It has been accepted for inclusion in Electronic Thesis and Dissertation Repository by an authorized administrator of Scholarship@Western. For more information, please contact [email protected]. PATHWAY-SPECIFIC SIGNALING AND ITS IMPACT ON FERTILITY: A FOCUS ON THE KISSPEPTIN RECEPTOR, Kiss1r (Thesis format: Monograph) by Maryse R. Ahow Graduate Program in Physiology A thesis submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy The School of Graduate and Postdoctoral Studies The University of Western Ontario London, Ontario, Canada © Maryse R. Ahow, 2014 Abstract Hypothalamic gonadotropin-releasing hormone (GnRH) is the master regulator of the neuroendocrine reproductive (HPG) axis and its secretion is regulated by various afferent inputs to the GnRH neuron. Activation of some Gαq/11-coupled receptors leads to GnRH neuronal membrane depolarization and GnRH secretion. The most potent trigger of GnRH secretion is kisspeptin (KISS1), the ligand for the Gαq/11-coupled receptor, KISS1R. The critical role for the KISS/KISS1R system in reproduction is revealed in patients bearing KISS1R mutations causing reproductive axis dysfunction. Furthermore mice carrying targeted KISS1R deletion phenocopy human patients in being infertile and hypogonadotropic. While studies have shown that Kiss1r signaling is essential for attaining and maintaining fertility the underlying mechanisms have not been fully elucidated. Our overall goal of this study was to reveal novel signaling mechanisms downstream of Kiss1r that regulate GnRH secretion and fertility. We recently demonstrated that in addition to Gαq/11, Kiss1r also signals to ERK1/2 via the β-arrestin pathway. Here we investigated the role of this β-arrestin signaling in Kiss1r-dependent Gnrh secretion. Using mice lacking β- arrestin, we determined that Kiss1r triggers significant Gnrh secretion via the β-arrestin pathway. Thus, mice use both the Kiss1r-coupled Gαq/11 and β-arrestin cascades to regulate Gnrh secretion and thereby, fertility. In addition to β-arrestins, Kiss1r potentially uses other Gαq/11-independent signaling pathways to regulate fertility. To test whether these pathways are sufficient to attain and maintain fertility we created Gnrh neuronal-specific Gαq/11 knockout mice and characterized their reproductive development and capacity to trigger Gnrh secretion following KISS1 administration. While these mice were hypogonadotropic and had delayed pubertal onset they retained partial fertility and ability to trigger Gnrh secretion in response to KISS1 stimulation confirming that Kiss1r-Gαq/11-independent signaling is sufficient for attaining and maintaining fertility. Overall, we show that Kiss1r signals via both Gαq/11-dependent and -independent mechanisms to regulate Gnrh secretion and fertility. We also demonstrated that one of these Gαq/11-independent pathways is mediated by β-arrestins in mice. Based on these novel findings, the potential now exists to develop new molecular strategies to treat infertility in humans. Keywords: KISS1R, IHH, L148S, β-arrestin, Gαq/11, GnRH, LH, FSH, HPG axis ii Co-Authorship Statement This dissertation incorporates material that is the result of collaborative research efforts and all studies were carried out under the supervision of Dr. Andy Babwah. The following additional collaborators have made a significant contribution to the completion of particular studies and deserve recognition: 1. Dr. Stuart Tobet and Connor Nash evaluated GnRH neuronal populations in perfused brains of embryonic and adult mice (Figs. 2.1, 2.2 and 2.16). 2. Dr. Ursula Kaiser’s lab verified preliminary data from the Babwah laboratory that L148S triggers ERK1/2 phosphorylation in HEK 293 cells and also demonstrated the inability of L148S to trigger kisspeptin stimulated InsP3 formation compared to WT KISS1R (Figs. 2.5D, 2.6 and 2.9). 3. Dr. Macarena Pampillo performed the L148S-dependent ERK1/2 phosphorylation assay in mouse embryonic fibroblasts (MEFs) lacking β-arrestin (Fig. 2.8). 4. Dr. Macarena Pampillo crossed parental strains to obtain the experimental Gnaqfl/fl;Gna11-/-;Gnrh-Cre mice and control littermates as well as assisted with blood collection and surgeries. 5. Serum was analyzed for luteinizing hormone, follicle stimulating hormone and testosterone by the Endocrine Technology and Support Lab, Oregon National Primate Research Center, Beaverton, OR, USA. (Figs. 2.3, 2.4, 2.22 and 2.23). Animals were housed at the London Regional Cancer Program Animal Facility where vivarium staff provided general animal maintenance. I was responsible for the crossing, weaning, genotyping and maintenance of each mouse colony used in this dissertation. In addition to this I actively participated in all animal procedures and treatments including brain perfusions, dissections, surgeries tissue cryosectioning and blood collection and processing for hormone assays. Finally, unless otherwise stated above, I directly performed all other cell-related studies using a variety of cell lines (HEK 293, GT1-7, MEFs, and COS-7). iii Dedication To the graduate student who happens across this dissertation one day. Pressure makes diamonds so do not give up and remember that we have all been exactly where you are right now. iv Acknowledgments I am incredibly overwhelmed with the amount of love and support that I have been blessed to receive over the years. My deepest gratitude goes out to the teachers, professors, friends, family and colleagues who have shared knowledge or just inspired me to keep working. This accomplishment is as much yours as it is mine – thank you. Words alone are not enough to express the unfailing support I received from my parents. Although they were miles away and I missed them dearly, their prayers and words of encouragement went a long way in carrying me through the rough times. At times when I was at my weakest they reminded me that if “God brings you to it He will bring you through it” and I’ve come to realize this truth regardless of religious persuasion. I also want to thank the members of my advisory committee for all the helpful suggestions with special thanks to Dr. Bonnie Deroo for words of encouragement and Dr. Daniel Hardy who patiently read and offered corrections for my thesis. Dr. Macarena Pampillo was invaluable in the laboratory for sharing skills, expertise and to troubleshooting new techniques. The lab could not function without her and I cannot thank her enough for all the assistance and guidance over the years. Last but not least, thank you Dr. Babwah for opening your lab to give an amazing opportunity to an international student. Your generosity, guidance and advice over the years will never be forgotten and working with you has truly been a rewarding experience. v Table of Contents Abstract ............................................................................................................................... ii Co-Authorship Statement................................................................................................... iii Dedication .......................................................................................................................... iv Acknowledgments............................................................................................................... v Table of Contents ............................................................................................................... vi List of Tables ...................................................................................................................... x List of Figures .................................................................................................................... xi List of Abbreviations ....................................................................................................... xiv List of Appendices .......................................................................................................... xvii Chapter 1: Literature Review .............................................................................................. 1 1.1 The reproductive axis .............................................................................................. 1 1.2 Gonadotropin Hormone Releasing (GnRH) Neurons ............................................. 1 1.2.1 Biological systems for studying GnRH neurons ......................................... 7 1.2.2 Regulation of GnRH secretion .................................................................... 8 1.3 Kisspeptin and the Kisspeptin receptor................................................................. 10 1.3.1
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