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Identification of Hypothalamic Sites That Control Puberty Onset and Sexual Maturation

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Identification of Hypothalamic Sites That Control Puberty Onset and Sexual Maturation Identification of hypothalamic sites that control puberty onset and sexual maturation by Megan Louise Greenwald-Yarnell A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Neuroscience) in the University of Michigan 2013 Doctoral Committee: Professor Martin G. Myers, Jr., Chair Professor Robert Denver Professor Michael Lehman, University of Mississippi Medical Center Professor Sue Moenter Assistant Professor David Olson Professor Audrey Seasholtz Basic research is what I'm doing when I don't know what I'm doing. - Wernher von Braun © Megan Louise Greenwald-Yarnell 2013 Dedication Dedicated to my amazing husband, James. I am eternally grateful for your never-ending love, understanding and encouragement. ii Acknowledgements I’d like to acknowledge the support of my mentor, Martin Myers, and the entire Myers lab- past and present. The culture of cooperation and teamwork that Martin expects in his lab has made my time there truly enjoyable. I am so thankful that he welcomed me into the lab and allowed me to pursue my research interests, despite the fact that at times they were so very different from what the rest of the lab was working on. I’d like to thank Dr. Christa Patterson who has been so instrumental in my success in lab and also in maintaining my sanity over the years. Thank you to Meg Allison and Amy Sutton for the evenings of pizza and drinks in lab and for always being available to talk- whether the topic is science or personal. Without the guidance of former lab members Drs. Rebecca Leshan, Gwen Louis, Scott Robertson, Eneida Villanueva and Darren Opland early on, none of this would have been possible. I’d also like to thank Dr. Dave Olson, who has the unfortunate position of running the lab adjacent to Martin’s and has had to suffer my outbursts and fill in for Martin when he’s out of town and I desperately need to discuss some recently acquired data. To Drs. Courtney Marsh and Josh Skorupski- thank you for your help with these projects and for your willingness to provide the clinical perspective. Thank you to my classmates, the Neuroscience Graduate Program iii incoming class of 2008- I never would have made it through the early days of grad school without you guys. I’d also like to thank Jocelyn, Ariana and Tracy for your support over the past year, especially during Jim’s recent deployment. I’d also like to acknowledge the contributions of our collaborators, Drs. Suzanne Moenter and Carol Elias as well as their lab members. Additionally, I’d like to thank my dissertation committee for their contributions. Your assistance with this research has been invaluable and is greatly appreciated. And finally, thank you to my family. You have all been so understanding over the past five years when science demanded all my time, energy and focus. Without your encouragement and support, I never would have had the courage or stamina to accomplish this. iv Table of Contents Dedication .............................................................................................................ii Acknowledgements .............................................................................................. iii List of Figures ...................................................................................................... vii Chapter 1 - Introduction ........................................................................................ 1 Chapter 2 - Genetic ablation of LepRb from Nos1-expressing neurons ............ 33 Methods .......................................................................................................... 36 Results ............................................................................................................ 39 Conclusions & Discussion ............................................................................... 44 Chapter 3 - Estrogen acts via ERα in kisspeptin/neurokinin B neurons to mediate feedback on the reproductive axis and control the onset of puberty in female mice .................................................................................................................... 53 Methods .......................................................................................................... 56 Results ............................................................................................................ 63 Conclusions & Discussion ............................................................................... 76 Chapter 4 – Direct estrogen action on Kiss1/ERα neurons is required for negative feedback on the reproductive axis of male mice ............................................... 100 Methods ........................................................................................................ 103 Results .......................................................................................................... 107 Conclusions & Discussion ............................................................................. 112 Chapter 5 – Summary & Conclusions ............................................................... 122 v The role of direct leptin action on Nos1-expressing hypothalamic neurons ... 122 Regulation of the reproductive axis by estrogen action via ERα on kisspeptin neurons ......................................................................................................... 127 References ....................................................................................................... 137 vi List of Figures Chapter 1 Figure 1- The hypothalamic-pituitary-gonadal (HPG) axis ................................. 32 Chapter 2 Figure 2 - Generation of LeprNos1KO mice ......................................................... 48 Figure 3 - Reproductive effects of ablation of LepRb from Nos1-expressing neurons ............................................................................................ 49 Figure 4 - Body mass is increased in both female and male LeprNos1KO mice .. 50 Figure 5 - ARC Pomc gene expression is altered in LeprNos1KO mice ............... 51 Figure 6 - Sexually dimorphic alteration in T4 levels in LeprNos1KO mice .......... 52 Chapter 3 Figure 7- Generation of mice to study Kiss1- and Tac2-expressing neurons .... 81 Figure 8 – Dual-label in situ hybridization/immunohistochemistry in Tac2eYFP and Kiss1eYFP female mice ...................................................................... 82 Figure 9 – Co-expression of ERα and eYFP in Tac2eYFP and Kiss1eYFP female mice .................................................................................................. 83 Figure 10 - Body mass and composition of female mice lacking ERα in either Kiss1- or Tac2-expressing neurons ................................................. 85 Figure 11- Precocious but incomplete reproductive maturation in the absence of ERα from either Kiss1- or Tac2-expressing neurons ........................ 87 Figure 12 – Ovarian and uterine phenotype of adult female mice lacking ERα in Kiss1- or Tac2-expressing neurons .................................................. 88 Figure 13 - Gonadotropin and gonadal hormone levels of intact adult females . 89 Figure 14 - Gonadotropin and gonadal hormone levels of intact juvenile females ......................................................................................................... 90 Figure 15 - Effect of ovariectomy and acute estradiol treatment on LH and FSH vii levels ................................................................................................ 91 Figure 16 - Altered ARC gene expression in intact female mice lacking ERα in either Kiss1- or Tac2-expressing neurons ........................................ 92 Figure 17 – Kiss1 expression in the AVPV/PeN of intact females is diminished only in ERαKiss1KOs .......................................................................... 93 Figure 18 – Ovariectomy results in gene expression changes in the ARC that mimic loss of ERα from either Kiss1- or Tac2-expressing neurons .. 94 Figure 19 – AVPV/PeN Kiss1 expression is diminished as a result of ovariectomy or ablation of ERα from all Kiss1-expressing neurons . 95 Figure 20 - ARC kisspeptin peptide levels are unchanged by ablation of ERα from either Kiss1- or Tac2-expressing neurons ................................ 97 Figure 21 – AVPV/PeN kisspeptin peptide levels are reduced when ERα is ablated from Kiss1-expressing neurons ........................................... 99 Chapter 4 Figure 22 - Generation of mouse models to study Kiss1- and Tac2-expressing neurons in males ............................................................................ 115 Figure 23 – Co-expression of eYFP and ERα in the hypothalamus of male Kiss1eYFP and Tac2eYFP mice .......................................................... 116 Figure 24 - Kisspeptin immunoreactivity in the rostral hypothalamus of Kiss1eYFP male and female mice .................................................................... 117 Figure 25 - Body mass and composition are unchanged in ERαKiss1KO and ERαTac2 KO male mice ................................................................... 118 Figure 26 – Male reproductive organ weights are affected by ablation of ERα from either Kiss1- or Tac2-expressing neurons .............................. 119 Figure 27 – Gonadotropin and gonadal hormone levels are altered by ablation of ERα from all Kiss1- but not Tac2-expressing neurons ................... 120 Figure 28 - Gene expression in the rostral hypothalamus and ARC ................ 121
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