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The Role of the Wnt-Signaling Pathway in Somite Formation During Embryonic Development Alexander Aulehla

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The Role of the Wnt-Signaling Pathway in Somite Formation During Embryonic Development Alexander Aulehla About gradients and oscillations : the role of the Wnt-signaling pathway in somite formation during embryonic development Alexander Aulehla To cite this version: Alexander Aulehla. About gradients and oscillations : the role of the Wnt-signaling pathway in somite formation during embryonic development. Embryology and Organogenesis. Université Pierre et Marie Curie - Paris VI, 2008. English. NNT : 2008PA066106. tel-00811623 HAL Id: tel-00811623 https://tel.archives-ouvertes.fr/tel-00811623 Submitted on 10 Apr 2013 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. THESE DE DOCTORAT DE L’UNIVERSITE PIERRE ET MARIE CURIE Spécialité Biologie du Développement--La logique du vivant Présentée par M. Alexander AULEHLA Pour obtenir le grade de DOCTEUR de l’UNIVERSITE PIERRE ET MARIE CURIE A propos de gradients et d’oscillations: le rôle de la voie de signalisation Wnt dans la formation des somites au cours du développement embryonnaire Soutenue le 18 septembre 2008 devant le jury composé de: M. le Pr. Olivier POURQUIE Directeur de thèse Mme le Pr. Muriel UMBHAUER Examinateur M. le Pr. Albert GOLDBETER Rapporteur M. le Pr. Julian LEWIS Rapporteur dedicata a Mirabel 2 Acknowledgments I’m deeply grateful to Olivier Pourquié for the opportunity to prepare this thesis. The positive experience in his laboratory and his enthusiasm for research definitively contributed to my decision in favor of a career in basic research and I’m very thankful for this. I would like to thank Prof. Albert Goldbeter and Prof. Julian Lewis for their time and effort in evaluating my thesis as rapporteurs and for being part of the jury. I would like to thank Prof. Muriel Umbhauer for being in the jury of my thesis. I’m very much indebted to Prof. Bernhard Herrmann for his guidance during the time in his laboratory in Freiburg. His view of research clearly was an important influence for my future approach to science. I thank the Swiss Foundation for Medical-Biological Grants/ Swiss National Science Foundation for their financial support. I thank my colleagues in the laboratory in Kansas City. Only through the scientific discussion with them could my research progress and the ideas mature. I would like to thank the managers and technicians, both in our lab as well as in the core facilities at the Stowers Institute. Their great help is highly appreciated. I thank Bertrand Bénazeraf for this critical reading of my thesis. The help of Joanne Chatfield in writing, editing and finalizing this thesis can not be appreciated high enough. I’m very appreciative for the constant support by our families - grazie. I’m thankful to my children Nina and Dante for the joy and meaning they bring to our lives. Most of all, I wish to thank Mirabel for her loving support. I feel very fortunate to have her by my side; she has everything I am dreaming of. 3 Dans l’échange entre la théorie et l’expérience, c’est toujours la première qui engage le dialogue. C’est elle qui détermine la forme de la question, donc les limites de la réponse. François Jacob, La logique du vivant 4 TABLE OF CONTENTS Résumé.................................................................................................................................7 Summary..............................................................................................................................8 Résumé substantiel...............................................................................................................9 1. Introduction..................................................................................................................12 1.1 Body segmentation in vertebrates.............................................................................12 1.1.1 Somite nomenclature ..........................................................................................14 1.1.2 The epithelial somite and its derivatives.............................................................15 1.1.3 Somite polarity....................................................................................................17 1.1.4 Resegmentation...................................................................................................18 1.1.5 Axial identity of vertebrae ..................................................................................18 1.1.6 Changing perspective − the presomitic mesoderm as the site of action .............19 1.1.7 Segmentation and epithelialization are distinct processes..................................20 1.1.8 Somite number control—an example of regulative development ......................21 1.2 Early theoretical models ...........................................................................................23 1.2.1 The clock and wavefront model..........................................................................23 1.2.2 Meinhardt’s reaction-diffusion model ................................................................25 1.3 Molecular mechanisms in somitogenesis...............................................................28 1.4 On periodicity and directionality of somitogenesis ...............................................29 2. Goal of this work..........................................................................................................38 3. Results ...........................................................................................................................39 3.1 Wnt3a plays a major role in the segmentation clock controlling somitogenesis......39 3.2. Real-time imaging of the somite segmentation clock..............................................52 3.2.1. Establishment of static culture conditions .........................................................53 3.2.2. Generation of a dynamic, fluorescent-based reporter protein............................57 3.2.3. Real-time imaging using two-photon microscopy.............................................61 3.2.4. Data analysis ......................................................................................................65 3.2.4.1 Oscillation period vs. cycle period...................................................................65 3.3 A -catenin gradient links the clock and wavefront systems in mouse embryo segmentation ...................................................................................................................72 4. Discussion......................................................................................................................89 4.1 Wnt-signaling oscillations indicate a complex signaling network within the segmentation clock..........................................................................................................89 4.2 Wnt signaling is graded as well as oscillatory in the PSM of mouse embryos ........92 4.3 The importance of experimental design....................................................................95 4.4. About gradients without positional information......................................................96 4.4.1 Mesp2 is segmentally expressed in the absence of the Wnt-signaling gradient ..100 4.4.2 Oscillations still slow down along the PSM in the absence of the Wnt-signaling gradient .........................................................................................................................102 4.5 An iconoclastic proposal: the clock is not the clock...............................................105 4.6 The Appendix model...............................................................................................107 5 4.7 Outlook ................................................................................................................114 5. References................................................................................................................115 6 Résume Une caractéristique fondamentale des vertébrés est leur organisation métamerique, visible au niveau de la colonne vertébrale. Cette organisation se met en place au cours du développement embryonnaire et l’émergence des précurseurs des vertèbres, les somites, formés à partir du mésoderm paraxial présomitique (PSM). Depuis la découverte d’une activité transcriptionelle oscillatoire de la voie de signalisation Notch dans le PSM, on propose que cette activité oscillatoire représente l’action d’une horloge embryonnaire, l’horloge de segmentation, responsable de contrôler la formation des somites de façon périodique. Dans cette étude, je présente la découverte d’une nouvelle association de la voie Wnt avec l’horloge de segmentation en décrivant l’activité oscillatoire de Axin2, une cible de la voie Wnt, dans le PSM. Ensuite, j’ai mise en place un system d’imagerie bi- photon qui nous permet d’observer l’action de l’horloge de segmentation en temps réel et in vivo dans les embryons de souris. Ce système permet de mesurer directement les paramètres des oscillations. Ultérieurement je décris la découverte d’un gradient d’expression de la protéine -caténine dans le PSM. A l’aide d’expériences de recombinaisons homologues conditionnelles nous avons déterminé que
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