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Dynamics of Hair Follicle Morphogenesis and Skin Homeostasis

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Dynamics of Hair Follicle Morphogenesis and Skin Homeostasis Dynamics of Hair Follicle Morphogenesis and Skin Homeostasis by Arlee L. Mesler A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy (Cellular and Molecular Biology) in the University of Michigan 2018 Doctoral Committee: Assistant Professor Sunny Y. Wong, Chair Professor Andrzej A. Dlugosz Associate Professor Marina Pasca di Magliano Professor Linda C. Samuelson Arlee L. Mesler [email protected] ORCID iD: 0000-0003-3510-4929 © Arlee L. Mesler 2018 Acknowledgements The work presented in this dissertation would not have been possible without the help of many talented and dedicated individuals in both my personal and professional life. First, I would like to acknowledge my mentor Dr. Sunny Wong. The passion you have for science and the precision with which you address scientific questions is inspiring. Thank you for helping me develop as a scientist and pushing me to think critically and always ask questions. I appreciate that you were always around to talk science and even help with experiments. Finally, thank you for supporting my interests outside of lab. I would also like to thank my committee members, Dr. Andrzej Dlugosz, Dr. Linda Samuelson, and Dr. Marina Pasca Di Magliano. Thanks first to Anj whose thoughtful questions during lab meetings propelled my projects forward. Thank you to Linda and Marina for always providing critical feedback and encouraging me to consider alternative explanations for my data. I walked away from each committee meeting feeling optimistic and excited by the feedback I received. I feel so fortunate to have had the support of such excellent scientists throughout my graduate career. I am so lucky to have been a member of the CMB graduate program. The diversity in research topics helped keep me up to date on scientific happenings outside of skin and hair biology. Thank you to Dr. Robert Fuller and the CMB support staff ii (Cathy Mitchell, Margarita Bekiares, Jim Musgrave, Pat Ocelnik, and Jessica Kijek) for helping me navigate every stage of graduate school. Also, a big thank you to members of the Wong lab, past and present. You’ve made coming into lab the past 4 years a fun, exciting experience. Alicia, Jacob and Jamie, thank you for always keeping the lab running smoothly. Thanks to Markus, Shelby, Natalia, and Kenny for countless scientific discussions and for providing advice on experiments, presentations and life. I would also like to acknowledge members of the Dlugosz lab who provided key feedback during weekly lab meetings and were great neighbors. I would like to thank my mentors at my undergraduate institution, Humboldt State University. It was under their mentorship that I first realized how powerful and exciting conducting research could be. The passion I developed at HSU helped me navigate the ups and downs of graduate school. Thanks to my friends in Ann Arbor who’ve kept me sane and always been available for coffee breaks, happy hours, trivia, and trips to Chipotle. You’ve made graduate school so much fun and I cherish the memories we’ve made together. Finally, I would like to thank my family for their unwavering support. Thank you for believing in me and helping me reach my goals. iii Table of Contents Acknowledgements ....................................................................................................... ii List of Figures ............................................................................................................... x List of Tables .............................................................................................................. xiii Abstract ....................................................................................................................... xiv Chapter I: Introduction .................................................................................................. 1 1.1 Summary .................................................................................................................. 1 1.2 Hair Follicle Biology ................................................................................................ 2 1.21 Introduction .................................................................................................................... 2 1.22 Hair Follicle Structure ..................................................................................................... 3 1.23 Hair Follicle Stem Cells .................................................................................................. 5 1.24 Hair Follicle Development ............................................................................................... 7 1.25 Hair Canal Formation ..................................................................................................... 9 1.26 The Hair Cycle ..............................................................................................................11 1.27 Matrix Progenitors and Anagen .....................................................................................12 1.3 Signaling Pathways Driving Hair Follicle Morphogenesis and Homeostasis .. 13 1.31 Introduction ...................................................................................................................13 iv 1.32 Wnt/β-catenin ................................................................................................................14 1.33 Hedgehog .....................................................................................................................15 1.34 Bone Morphogenetic Proteins .......................................................................................17 1.35 Notch .............................................................................................................................18 1.36 Hair Placode Induction ..................................................................................................19 1.37 Hair Follicle Organogenesis and Differentiation .............................................................21 1.38 Hair Follicle Regeneration .............................................................................................23 1.4 Epidermal Barrier Formation and Harlequin Ichthyosis .................................... 25 1.41 Introduction ...................................................................................................................25 1.42 Clinical Features of Harlequin Ichthyosis .......................................................................28 1.43 Mutations in ABCA12 Underlie Harlequin Ichthyosis .....................................................29 1.44 Mouse Models of Harlequin Ichthyosis ..........................................................................31 1.5 Dissertation Summary .......................................................................................... 32 1.6 Figures ................................................................................................................... 34 1.7 Reference List........................................................................................................ 42 Chapter II: Hair Follicle Terminal Differentiation is Orchestrated by Distinct Early and Late Matrix Progenitors ....................................................................................... 57 2.1 Summary ................................................................................................................ 57 2.2 Introduction ........................................................................................................... 57 2.3 Experimental Procedures ..................................................................................... 60 2.31 Mice ..............................................................................................................................60 v 2.32 5E1 Experiments ...........................................................................................................60 2.33 Immunohistochemistry ..................................................................................................61 2.34 Antibodies .....................................................................................................................61 2.35 Quantitating Shh+/EGFP+ Matrix Cell Contribution to Differentiated Cell Layers ............62 2.36 Lineage Tracing and Quantitating Shh-CreERT2;R26R-YFP Matrix Cell Contribution to Differentiated Cell Layers ......................................................................................................63 2.4 Results ................................................................................................................... 64 2.41 Asynchronous Formation of Terminally Differentiated Cell Layers in the Hair Follicle ....64 2.42 The CL is Specified Prior to Canonical K75 and K6 Expression ....................................65 2.43 Early Matrix Progenitors Give Rise to K79+ Cells ..........................................................67 2.44 Early and Late Matrix Progenitors Exhibit Molecular Differences ...................................69 2.45 Neither BMP signaling, Shh nor DP Maturation is Required for Early Matrix Cell Differentiation ........................................................................................................................70 2.46 Asynchronous Maturation of Terminally Differentiated Cell Layers ................................72 2.47 Fate of Terminally Differentiated CL Cells .....................................................................73 2.48 Functional
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