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The Role of ATP-Dependent Chromatin Remodeling Enzyme CHD7 in the Development and Maintenance of Murine Neural Stem Cells By

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The Role of ATP-Dependent Chromatin Remodeling Enzyme CHD7 in the Development and Maintenance of Murine Neural Stem Cells By The role of ATP-dependent chromatin remodeling enzyme CHD7 in the development and maintenance of murine neural stem cells by Joseph Anthony Micucci A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Biological Chemistry) in the University of Michigan 2013 Dissertation Committee: Associate Professor Donna M. Martin, Co-Chair Adjunct Assistant Professor Daniel A. Bochar, Co-Chair Assistant Professor Shigeki Iwase Associate Professor Raymond C. Trievel Professor Michael D. Uhler Associate Professor Anne B. Vojtek When I heard the learn’d astronomer; When the proofs, the figures, were ranged in columns before me; When I was shown the charts and the diagrams, to add, divide, and measure them; When I, sitting, heard the astronomer, where he lectured with much applause in the lecture-room, How soon, unaccountable, I became tired and sick; Till rising and gliding out, I wander’d off by myself, In the mystical moist night-air, and from time to time, Look’d up in perfect silence at the stars. Walt Whitman Leaves of Grass. 1900 Never give up! Trust your instincts! Peppy Hare Star Fox 64 1997 © Joseph Anthony Micucci 2013 Dedication To Kristen, Thank you for supporting me and keeping me grounded for the last 10 years, much to your own chagrin. ii Acknowledgements First, I would like to thank my incredible wife, Kristen. I have no idea how we made it through the last five and a half years with our marriage and happiness intact. I think we would both agree that the cats were excellent arbiters. There is absolutely no way that I could have finished graduate school without you. You are the motivating and grounding force in my life for which I am eternally grateful; otherwise, I would never accomplish anything besides being comfortable on the couch watching football. I will do my best to ensure that the next phase in our lives goes much more smoothly and pleasantly than the previous. There are no words that can adequately express my gratitude to my parents for their unrelenting positivity and unconditional love throughout my life. Despite all of the precocious shenanigans I put you through in the early years of grade school, having you drive me up and down the East Coast to play hockey and paying for my education at Penn State (granted, you two had almost as much fun there as I did), you have never once been anything less than supremely supportive by letting me make my own life decisions and learn from my mistakes. Thank you to my grandparents for always being there for me regardless of their geographical location. I would also like to thank my family for their all of their love and support. I have to specifically thank Aunt Peg and Uncle iii Joe for their hospitality whether Kristen and I were with them in South Bend, Ann Arbor or Pittsburgh. We both really appreciated being treated like one of your own children whenever we were at your house for holidays that we couldn’t make it back to Jersey or Philly. Thank you to all of our friends back East (and West now for Robert and Imee) for always meeting us at crazy hours and locations during the holidays and our brief vacations. I look forward to making up for lost time when we return to Philadelphia. I would also like to thank my friends and lab mates in Ann Arbor. Thanks to Joel and Bruce for their excellent ability to help me forget about things that are troubling me, largely through ridiculous conversations and excessive amounts of playing video games. At times, I’m still completely shocked that we all graduated in reasonable amounts of time. I would like to thank everyone that I have worked with in the Martin Lab, specifically Wanda, Mindy, Mark, Jennifer, Ethan and Sophie. It was a pleasure to come to lab and deal with such fun people. I retroactively apologize for my insane sense of humor and relative lack of filter. I don’t think there is enough space in this dissertation to thank Liz Hurd. Our relationship started out as that of master and apprentice and evolved into some bizarre amalgamation of sister/mother/work-wife. Whatever it was, thank you for it! I don’t think I would have adequately made the transition from Dan’s lab to Donna’s lab without your guidance. Kristen and I greatly appreciate your hospitality and absorbing us into your family. I’m also sorry for putting your cat in a bag and for him giving me necrotizing fasciitis. iv I also need to thank Becky Simon for always being up for crying in our beers/Captain and Coke’s whenever I needed it. Our friendship may have begun on that fateful van ride to Kalamazoo first year with discussions of diabetes, Wilford Brimley and Crohn’s disease, but I think it was solidified when both of us were crying when Penn State locked up the Rose Bowl bid in 2008. Granted, I was crying because my alma mater won the Big Ten championship and you were crying because the Spartans had just been curbstomped by four touchdowns at the feet of the Nittany Lions, but whatever. I would also like to thank my thesis committee: Ray Trievel, Mike Uhler, Anne Vojtek, Shigeki Iwase and Tom Glaser. Without your patience and guidance throughout the last five years, I would not be prepared to write a dissertation and defend it. Lastly, I would like to thank my mentors. Dan, thank you for giving me the freedom to be myself, make mistakes and learn from them. It’s sad that I didn’t get to finish my thesis research in your lab, but I thoroughly enjoyed every second that I got to learn from you. Donna, thank you for giving me boundaries when I needed them and putting me into the right positions to succeed. Also, thank you for taking me in when I needed help the most. I know that we don’t often see things the same way, but I’m fairly certain that we’ve learned a great deal from eachother. I couldn’t have asked for better mentors, despite being polar opposite in your outlooks on life and science. You two were exactly what I needed at exactly the right times. v Table of Contents Conte Dedication .............................................................................................................ii Acknowledgements .............................................................................................. iii List of Figures .......................................................................................................ix List of Tables ........................................................................................................xi Abstract ............................................................................................................... xii Chapter 1: Introduction ........................................................................................ 1 SVZ neural stem cell function during corticogenesis ......................................... 1 SVZ neural stem cell function during olfactory bulb neurogenesis .................... 3 Signaling pathways in SVZ neurogenesis ......................................................... 5 Wnt Signaling ............................................................................................... 5 Growth Factor Signaling ............................................................................... 6 Hedgehog Signaling ..................................................................................... 7 Retinoic Acid Signaling ................................................................................ 8 Epigenetic regulation of SVZ neurogenesis ...................................................... 9 Histone modifying enzymes ....................................................................... 10 ATP-dependent chromatin remodeling enzymes ....................................... 11 Structure and function of the CHD superfamily ............................................... 12 vi CHD family members and their functions in stem cells ................................... 14 CHD proteins and embryonic stem cells .................................................... 14 CHD proteins and mesenchymal stem cells ............................................... 15 CHD proteins and hematopoietic stem cells .............................................. 16 CHD proteins and neural stem cells ........................................................... 16 CHD7 and stem cells ...................................................................................... 18 CHD7 and CHARGE syndrome ...................................................................... 20 Novel insights into CHD7 regulation of SVZ neural stem cells ........................ 22 References ...................................................................................................... 31 Chapter 2: CHD7 and retinoic acid signaling cooperate to regulate neural stem cell and inner ear development in mouse models of CHARGE syndrome .......... 41 Abstract ........................................................................................................... 41 Introduction ..................................................................................................... 42 Materials & Methods ....................................................................................... 44 Results ............................................................................................................ 54 Discussion....................................................................................................... 65 Acknowledgements ......................................................................................... 69 References .....................................................................................................
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