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RDH10 Is Necessary for Initial Vagal Neural Crest Cell Contribution to Embryonic Gastrointestinal Tract Development

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RDH10 Is Necessary for Initial Vagal Neural Crest Cell Contribution to Embryonic Gastrointestinal Tract Development RDH10 is Necessary for Initial Vagal Neural Crest Cell Contribution to Embryonic Gastrointestinal Tract Development BY © 2015 Naomi Elaine Butler Tjaden Submitted to the graduate degree program in Anatomy and Cell Biology and to the Graduate Faculty of The University of Kansas Medical Center in partial fulfillment of the requirements for the degree of Doctor of Philosophy. Paul Trainor, Co-Chairperson Brenda Rongish, Co-Chairperson Timothy Fields Dale Abrahamson Osama Almadhoun Paul Cheney Date Defended: May 1, 2015 The Dissertation Committee for Naomi Elaine Butler Tjaden Certifies that this is the approved version of the following dissertation: RDH10 is Necessary for Initial Vagal Neural Crest Cell Contribution to Embryonic Gastrointestinal Tract Development Paul Trainor, Co-Chairperson Brenda Rongish, Co-Chairperson Date approved: May 5, 2015 ii Abstract Retinol dehydrogenase 10 (RDH10) catalyzes the first oxidative step in the metabolism of vitamin A to its active form retinoic acid (RA). Insufficient or excess RA can result in various congenital abnormalities, such as Hirschsprung disease (HSCR). In HSCR, neurons are absent from variable lengths of the gastrointestinal tract due to a failure of neural crest cell (NCC) colonization or development, leading to megacolon and/or the failure to pass meconium. Enteric neurons are derived from neural crest cells (NCC); hence HSCR is associated with incomplete NCC development or colonization of the GI tract. We investigated our hypothesis that RDH10 is necessary for proper NCC contribution to the enteric nervous system (ENS). The mouse point mutant Rdh10trex/trex exhibits decreased retinoid signaling and colonic aganglionosis. Organ explant culture and in utero retinal supplementation experiments define a temporal requirement for RA in ENS development between E7.5-E9.5. Tamoxifen-inducible temporal deletion of RDH10 at E6.5-E7.5 confirms this early retinal role, while later RDH10 deletion suggests retinal independence for continued enteric NCC colonization. Removing RDH10 from NCCs shows no gross or ENS-specific neuronal defects, suggesting that RDH10 is not intrinsically required in enteric NCCs for proper colonization of the gut, but rather is necessary as a paracrine signal in the vagal NCC microenvironment. We investigated signaling cascades that are known to play a role in gut microenvironment maintenance that may be altered in these RDH10 mutants using both a targeted expression analysis approach as well as RNA-sequencing. Candidates include GDNF and its signaling family members such as RET and GFRα1, as well as extracellular matrix proteins. Novel models of HSCR, such as Rdh10trex/trex will improve our understanding of RA contribution to intestinal development and may lead to innovative non-surgical treatment approaches to reduce the morbidity and mortality of this common congenital disease. iii Acknowledgements I would like to thank Paul for being an incredible mentor. I am so lucky to have such an understanding, supportive and fun person to call my boss, I am so happy you gave me a chance to learn and grow in your lab for the last four years. I am so thankful for your approach of “raising” graduate students, for teaching me to think for myself, yet for pulling me back in when my ideas make no sense, and of course, for letting me work on such a fun project relating to my favorite pastime. To my committee members, Tim, Brenda, Osama, Dale and Uncle Paul, thank you for being such wonderful role models and for helping me become the best student I could be. And to the MD/PhD program, especially to Janice, Tim, Brenda and Dr. B., you have supported me from the day I came to Kansas City, and gave me a chance to pursue my dream as a physician-scientist, and I will forever be grateful. Thank you for everything you have taught me, Lisa. I hope to one day be able to think as clearly and critically as you do every day. Your words of encouragement, your advice on presentations, and your overall hip lifestyle have made such a big impact on the type of scientist and person I want to become. I am so happy you took the time to take me under your tiny trex wing and mentor me in the lab. To the Trainor lab members: for your insights, constructive (and not constructive) comments throughout my time in the lab, and importantly, for the amazing environment and comradery, thank you. To my “work wife,” Aude, je te remercie. For the thousands of coffee breaks we have taken over the last four years, the almost daily shared lunches, for all of our trips near and far, the hundreds of grams of calissons you have brought me from Paris, and for always being a patient friend and good listener when I need to vent. I know we will be life-long friends, even though you are Parisian. To Shachi, I am so grateful for your willingness to help me when I needed it most, even at the expense of your sleep. Your opinion means so much to me, and your dedication to your friends and colleagues is such an admirable trait, and I hope to be there for you, should you ever need me. Thank you, Annita and Jason (and Artemis!) for being such good friends in the lab, iv medical school and in real life. I have really loved our time together, not just because of the amazing food you both make, but because you both make me strive to be a better person. Kristin, I’m so happy we got to go through this process together, and thankful that you were always there to help double-check my calculations. You are such a hardworking person, a great scientist and I know you will be an excellent mother. And William, thank you for having more house problems than me, so my problems seem smaller. Melissa, my work would not be what it is without you. Thank you for doing such an amazing job with the mice, and for being a great travel buddy outside of work. I would also like to thank the Trainor lab alumni: Raul, for keeping us all entertained; for Kaz and his endless knowledge of experimental techniques and willingness to help; to Liang for the last 加油 which gave me my final boost; to Daisuke for introducing me to the amazing Japanese baymate culture; to Mama Kim for the heartfelt conversations and experimental help; and to Hiroshi, the most efficient, friendly, tolerant baymate I could have ever wished for. I am not sure what you did to Paul for him to punish you with such a loud, messy baymate for 3 years, but I am happy you did it. To the people at Stowers who have made this such a wonderful environment, which made coming to work every day fun, thank you. Robin, my work mom, thank you. You have supported me so much by just being yourself and keeping an eye out for me and helping to keep me out of trouble. You always manage to brighten my day every time I see you. To Carolyn and Shelly, THANK YOU x 1000! You both do so many things behind the scenes with no expectation of being thanked. If you two were not around, I think the Institute would collapse. To the histology ladies and back computer room guys, thank you for helping me with my incredible amount of problems! S-Bhatt, Marina and William, thank you for the last minute corrections and comment on this thesis, I know it was rough and I appreciate it! And thank you, Agne, for becoming such a supportive friend in the last year and for keeping my ego at bay when you crush me on the courts. Thank you, Jen (jpoo). You were an amazing lab manager, and I am so happy we became such good friends. You are truly a friend that puts others’ needs before her own, and I know I can always call on you when I need a hand, whether it is a chore around the v house or yard, a ride to the airport, to watch the pups or just to chat about life. I am so lucky to have someone like you in my life. To my best childhood, college, and med school friends: Betny, Hooly, Vkwan, Tiny Baby Lindsay Allan, and Allison, thank you for the fun times, and the rational (and sometimes irrational) advice. I appreciate what you have to say, and when you bring me out of the grad school blur and back into the world. I am so lucky to have you as friends. To my fellow Volkerites: Alan, Erin and John, April, Mary, Assassin Mike, Joe, Connor and Sarah, Elena and Travis and Nora and Alfie, Lynsi and Janete, Jackie and Emily, thank you for being such amazing neighbors, for tolerating my seemingly endless house construction and loud noises, for the borrowed cups of sugar, and for helping with Binker, Mateo, Cotton and Bruce at the drop of a hat. To the Tjaden family: Aunt Heidi and Mr. Bruce, you have taken me in as one of your own, and I am so lucky to have such wonderful and supportive in-laws, which I do not take for granted, although I do not tell you, “thank you,” enough. To Anne, I have been so blessed by watching you grow as a woman, scientist, and caregiver, and recently as one of my dearest friends. I know you will be successful in everything that you do (it’s not too late to choose MD/PhD!). And to Amanda, my long-lost sister, you have been there for me in more ways that anyone can ever know.
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