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Increased Fgf and Hh Signaling Impairs Craniofacial and Limb

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Increased Fgf and Hh Signaling Impairs Craniofacial and Limb INCREASED FGF AND HH SIGNALING IMPAIRS CRANIOFACIAL AND LIMB MORPHOGENESIS by LINNEA GWENDOLYN SCHMIDT B.A. Gustavus Adolphus College, 2011 A thesis submitted to the Faculty of the Graduate School of the University of Colorado in partial fulfillment of the requirements for the degree of Doctor of Philosophy Integrated Physiology Program 2017 This thesis for the Doctor of Philosophy degree by Linnea Gwendolyn Schmidt has been approved for the Integrated Physiology Program by Joan Hooper, Chair David Clouthier Lee Niswander Kathleen Connell Jim McManaman Trevor Williams, Advisor Date: 12/15/2017 ii Schmidt, Linnea Gwendolyn (Ph.D., Integrated Physiology) Increased FGF and HH Signaling Impairs Craniofacial and Limb Morphogenesis Thesis directed by Professor Trevor Williams ABSTRACT Tight regulation of signaling pathways during embryogenesis is required for normal development. In contrast, aberrations in signaling frequently result in fetal and infant mortality and morbidity. While the head and limb have separate evolutionary origins and dissimilar anatomy, many of the same genes and signaling pathways regulate craniofacial and limb development. As such, craniofacial and limb defects are often found together in genetic syndromes. The unique morphology of the head and limb is thus dependent upon the specific location, dosage, and timing of gene expression as well as genetic interactions between genes and signaling pathways. Using the mouse as a model system, the studies described in this thesis investigate the impact of increased FGF8 and HH signaling on craniofacial and limb development when increased starting at different embryological timepoints and from different tissues. The specific location, dosage, and timing of increased FGF8 and HH signaling led to distinct phenotypes and genetic interactions with other genes and signaling pathways. Together, these results contribute to the fields of embryogenesis, morphogenesis, and human congenital defects, with implications for the evolution of craniofacial and limb morphogenesis and therapeutic intervention in birth defects. The form and content of this abstract are approved. I recommend its publication. Approved: Trevor Williams iii Dedicated with love to my grandmothers, Bernice Olson Schmidt and Julia Andrew Gamon, who taught me learning is a lifelong pursuit. iv ACKNOWLEDGEMENTS Many people contributed to the successful completion of this dissertation. First, I would like to thank all the people who helped with the work presented here and offered advice and assistance. I am grateful to the past and present members of the Williams lab, particularly Eric Van Otterloo, Hong Li, Irene Choi, and Aftab Taiyab for their training and expertise. I would also like to acknowledge the members of my advisory committee for their suggestions along the way. Finally, I would like to especially thank my advisor, Trevor Williams, for his patient mentorship and guidance throughout this experience. I would also like to extend my appreciation to the members and administrators of the Integrated Physiology graduate program (formally Reproductive Sciences), with an especial thanks to Emily Busta, Ally Roof, and Sydney Coates for their unwavering support. Additionally, I would like to thank my Gustavus professors for their dedication to teaching and mentoring as well as their encouragement in pursuing graduate school Finally, all my gratitude to my family and friends that are outside of Colorado, but always inside my heart. I’m lucky to have both parents and grandparents who taught me the value in higher education and the pursuit of knowledge. Many thanks to my Minnesota Gusties—particularly Rebecca Rasp and Paul Huff –for giving me somewhere to come “home” to and Elisabeth Graeber for always giving me a great excuse for a European vacation. Finally thank you to my “Iowa Friends” -- Lena Thompson, Lisa Wehr Maves, Micah Stevens, Rachel Olson, and Ashley Christner -- for being with me since the very beginning and molding me into the person I am today. Our friendship is my greatest accomplishment. v TABLE OF CONTENTS CHAPTER I. THE GENETICS OF HEAD AND LIMB DEVELOPMENT........................................1 Introduction ............................................................................................................................ 1 Craniofacial Development ..................................................................................................... 1 Human Craniofacial Defects ........................................................................................ 2 Mouse Craniofacial Development ................................................................................ 8 Limb Development .............................................................................................................. 11 Human Limb Defects................................................................................................... 12 Mouse Limb Development........................................................................................... 12 Limb Patterning and Outgrowth ................................................................................. 14 Ossification in the Cranium and Limb ................................................................................. 18 Critical Signaling Pathways in Craniofacial and Limb Development ................................. 21 FGF Signaling ............................................................................................................ 22 Hedgehog (HH) Signaling .......................................................................................... 28 WNT Signaling ............................................................................................................ 35 BMP Signaling ............................................................................................................ 37 Layout of this Dissertation ................................................................................................... 39 II. MATERIALS AND METHODS ................................................................................... 41 Mice .................................................................................................................................. 41 vi Mouse Strains.............................................................................................................. 41 Genotyping .................................................................................................................. 44 Skeletal Analysis .................................................................................................................. 45 Bone & Cartilage Staining.......................................................................................... 45 Cartilage Staining ....................................................................................................... 45 Section Histochemistry................................................................................................ 46 In Situ Hybridization............................................................................................................ 46 Preparation of Probes................................................................................................. 46 Wholemount In Situ Hybridization (WMISH) ............................................................. 46 Section In Situ Hybridization ...................................................................................... 48 Skin Barrier Analysis ........................................................................................................... 49 Toluidine Blue ............................................................................................................. 49 Alkaline Phosphatase Staining ............................................................................................. 49 β-galactosidase Staining ...................................................................................................... 50 Whole Mount ............................................................................................................... 50 Sections ....................................................................................................................... 50 RNA Quantification ............................................................................................................. 51 Realtime PCR (qRTPCR) ............................................................................................ 51 RNAseq ........................................................................................................................ 52 III.. CCTSI CLINICAL EXPERIENCE ........................................................................... 54 vii Craniosynostosis .................................................................................................................. 54 Interactions with Patients in Clinic ...................................................................................... 55 Mice as a Model to Study Craniosynostosis ........................................................................ 60 Conclusions .......................................................................................................................... 61 IV. INCREASED FGF8 SIGNALING SHIFTS CELL FATE FROM OSTEOGENIC TO CHONDROGENIC IN THE DEVELOPING SKULL .................................. 63 Introduction .........................................................................................................................
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