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The Role of Pygopus 2 in Neural Crest

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The role of Pygopus 2 in Neural Crest KEVIN ROBERT GILLINDER A Thesis submitted for the Degree of Doctor of Philosophy Institute of Genetic Medicine Newcastle University April 2012 Abstract Epidermal neural crest stem cells (EPI-NCSC) are remnants of the embryonic neural crest that reside in a postnatal location, the bulge of rodent and human hair follicles. They are multipotent stem cells and are easily accessible in the hairy skin. They do not form tumours after transplantation, and because they can be expanded in vitro, these cells are promising candidates for autologous transplantation in cell replacement therapy and biomedical engineering. Pygopus 2 (Pygo2) is a signature gene of EPI-NCSC being specifically expressed in embryonic neural crest stem cells (NCSC) and hair follicle-derived EPI-NCSC, but not in other known skin-resident stem cells. Pygo2 is particularly interesting, as it is an important transducer of the Wnt signaling pathway, known to play key roles in the regulation of NCSC migration, proliferation, and differentiation. This study focuses on the role of Pygo2 in the development of the neural crest (NC) in vertebrates during development. Three loss-of-function models were utilized to determine the role Pygo2 in mouse and zebrafish development, and EPI-NCSC ex vivo. A Wnt1-specific loss of Pygo2 in mice causes multi-organ birth defects in multiple NC derived organs. In addition, morpholino (MO) knockdown of pygo homologs within zebrafish leads to NC related craniofacial abnormalities, together with a gastrulation defect during early embryogenesis. While ex vivo studies using EPI-NCSC suggest a role for Pygo2 in cellular proliferation. Overall, these results suggest that Pygo2 is required for the normal development of specific NC derived organs and cell types in a context dependent manner. i Acknowledgements First and foremost, I would like to take this opportunity to sincerely thank my supervisor, Dr Colin Miles for his endless support, guidance and encouragement. I have especially enjoyed our fruitful scientific discussions and the endless hot chocolates! Throughout my time at the Institute of Genetic Medicine, I have had the pleasure of working alongside a number of brilliant scientists from numerous laboratories. These have included past and present members of the Miles lab, Sieber-Blum lab, and the Muscle team. I thank them all for their friendship, scientific discussion and technical support. I would also like to acknowledge my collaborators and students: Dr Oliver Clewes for his assistance with real-time (qPCR) analysis of Pygo1 expression, Alla Narytnyk (MSc student), for assistance with analyses on the hair and skin, Linda Julian (MSc student), for contributions to analyses on the Me5 and brain, Professor Heather Cordell for assistance with statistical analysis of hair follicle stages, and Dr Owen Hughes and Ian Dimmick for assistance with FACS. Thanks also to Professor Steven Potter and Dr Robert Kelsh for providing the transgenic animal strains used in this study. Further thanks to Colin, Dr Steve Laval, and Professor Volker Straub for financial assistance towards the end of my studies – it is highly appreciated. In addition, I would also like to thank the many brave souls for manuscript proof reading in the final days, including Colin, Oli, Juliane, Owen, Lee, Carla and Sian. Finally, very special thanks go to my wife, Sian, for her constant care and support, and most importantly keeping me well fed. I also thank the rest of our families for their love, understanding, and support during this significant endeavour. ii TABLE OF CONTENTS Abstract ................................................................................................................................ i Acknowledgements ........................................................................................................ ii List of Figures ................................................................................................................ viii List of Tables .................................................................................................................... xi List of Abbreviations .................................................................................................... xii Chapter 1. Introduction .................................................................................................. 1 1.1 The Neural Crest ................................................................................................................ 1 1.1.1 Primary and secondary germ layers in vertebrate development ..................... 1 1.1.2 The fourth germ layer: formation of the NC ............................................................... 3 1.1.3 Specification of the Neural Crest ..................................................................................... 4 1.1.4 Migration and derivatives of the Neural Crest .......................................................... 5 1.1.5 NCSC are multipotent stem cells ...................................................................................... 7 1.1.6 Neurocristopathies: when things go wrong ............................................................... 8 1.1.7 Unifying features of the neural crest ............................................................................. 8 1.2 Epidermal Neural Crest Stem Cells .............................................................................. 9 1.2.1 EPI-NCSC are multipotent stem cells ............................................................................. 9 1.2.2 Therapeutic applications of EPI-NCSC ....................................................................... 10 1.2.3 An EPI-NCSC molecular signature ................................................................................ 10 1.3 Pygopus: discovery & function .................................................................................... 12 1.3.1 The importance of the Wnt pathway .......................................................................... 13 1.3.2 The canonical Wnt signaling cascade ......................................................................... 15 1.3.3 Non-canonical Wnt signaling ......................................................................................... 17 1.3.4 Differential expression and conservation of Pygopus ......................................... 18 1.3.5 Pygo is essential for Drosophila development ....................................................... 19 1.3.6 The dorso-ventral axis in Xenopus requires Pygopus ......................................... 21 1.3.7 A functional redundancy of Pygopus in mouse models ...................................... 22 1.3.8 A revised role of Pygopus in the Wnt pathway ...................................................... 23 1.3.9 Pygopus in disease .............................................................................................................. 24 1.3.10 Summary ................................................................................................................................. 25 1.4 Project aims ....................................................................................................................... 26 Chapter 2. Materials and Methods ........................................................................... 29 2.1 Bioinformatics .................................................................................................................. 29 iii 2.1.1 Database mining .................................................................................................................. 29 2.1.2 Protein Alignments ............................................................................................................. 30 2.2 Zebrafish Techniques ..................................................................................................... 31 2.2.1 Colony maintenance & embryo collection ................................................................ 31 2.2.2 Morpholino stock solutions ............................................................................................ 31 2.2.3 Microinjection of zebrafish embryos .......................................................................... 32 2.2.4 Live zebrafish imaging ...................................................................................................... 32 2.3 Mouse husbandry ............................................................................................................ 32 2.3.1 Colony maintenance ........................................................................................................... 32 2.3.2 Genotyping ............................................................................................................................. 33 2.4 Histology ............................................................................................................................. 33 2.4.1 Whole mount Alcian Blue & Alizarin Red S skeletal preparations ................. 33 2.4.2 Tissue fixation ....................................................................................................................... 33 2.4.3 Whole mount X-Gal staining of murine tissue ........................................................ 34 2.4.4 Sectioned on-slide X-gal staining of mouse brain ................................................. 34 2.4.5 Paraffin embedding of tissue .......................................................................................... 34 2.4.6 Tissue sectioning
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