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Molecular Understanding of Cytoneme-Based Wnt Trafficking

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Molecular understanding of cytoneme-based Wnt trafficking Zur Erlangung des akademischen Grades eines DOKTORS DER NATURWISSENSCHAFTEN (Dr. rer. nat.) von der KIT-Fakultät für Chemie und Biowissenschaften des Karlsruher Instituts für Technologie (KIT) genehmigte DISSERTATION von Benjamin Mattes 1. Referent: Assoc. Prof. Dr. Steffen Scholpp 2. Referent: Prof. Dr. Martin Bastmeyer Tag der mündlichen Prüfung: 17.10.2018 i ii iii Erklärung der Urheberschaft Ich erkläre hiermit an Eides statt, dass ich die vorliegende Arbeit selbstständig und ohne Benutzung anderer als der angegeben Hilfsmittel angefertigt habe. Die aus fremden Quellen direkt oder indirekt übernommenen Gedanken sind als solche gekennzeichnet. Des Weiteren habe ich die Satzung der Universität Karlsruhe (TH) zur Sicherung guter wissenschaftlicher Praxis in der jeweils gültigen Fassung beachtet. Diese Arbeit wurde bisher weder in gleicher noch in ähnlicher Form einer anderen Prüfungsbehörde vorgelegt und auch nicht veröffentlicht. Ort und Datum: Unterschrift: Karlsruhe, ........................................... .............................................. (Benjamin Mattes) iv v VI Abstract Cell-to-cell communication by signaling proteins is essential to orchestrate development and tissue homeostasis in all multicellular organisms. The highly conserved family of Wnt proteins are important guiding cues to control these processes. Fundamental to this complex signaling network are relatively small and defined signaling centers in a given tissue that produce and distribute Wnt proteins. Adjacent, larger groups of cells respond to these spatial and temporal information in a concentration-dependent manner and adjust their transcriptional program. However, a regulated sequence of morphogen activity is required to generate a fine-tuned communication network. Therefore, a controlled propagation machinery must ensure accurate signal distribution from the source to the surrounding tissue to initiate the correct developmental path. In this thesis, I consolidated the knowledge of the molecular machinery controlling cytoneme formation in zebrafish development. I expanded this principle to other aspects of Wnt signaling such as cancer growth and tissue homeostasis. Via a screening approach, I identified the receptor tyrosine kinase Ror2 as a promoting factor for cellular protrusions in general and particularly for Wnt8a cytonemes in cultured cells and in vivo. Consistently, I described the novel ligand-receptor pair Wnt8a and Ror2 by measuring the affinity for membrane accumulations and by biophysical imaging applications such as fluorescence correlation spectroscopy. Subsequently, functional interaction and transduction of the Wnt/PCP pathway was demonstrated during zebrafish convergence and extension and during non-canonical reporter activation in Xenopus. Wnt8a and Ror2 are considered to act in mutually repressive pathways, although the autocrine interplay for cytoneme formation to facilitate paracrine Wnt/β-catenin dissemination seems to be conserved. Thus, the model can be applied to other systems: The transcriptional β-catenin level and resulting proliferation of gastric cancer cells can be regulated by Ror2, thereby only disrupting the signal transmitting transport machinery in the source cells. Furthermore, I provided evidence of an ex vivo human stem cell organoid system, where growth and survival require cytoneme-mediated Wnt proteins from isolated myofibroblasts. Remarkably, this setup resembles an innovative approach for stem cell maintenance in the murine intestinal crypt and expands the potential roles of cytonemes in development, tissue homeostasis and diseases. VII VIII Acknowledgements I´m very grateful to Dr. Steffen Scholpp for providing me with the possibility to work on this fascinating project. I want to thank him for his guidance, encouragement, and scientific advice throughout all these years. I would like to thank Prof. Dr. Martin Bastmeyer to accept as my second referent and for evaluating my PhD thesis. I would like to thank Dr. Thomas Dickmeis and Dr. Gary Davidson for helpful advice and discussions as part of my TAC committee. I would like to thank all my previous Lab members who accompanied me in all the time at the ITG. I would especially thank Sabrina Weber, Dr. Bernadette Boesze, Dr. Eliana Stanganello, Dr. Simone Geyer, and Yonglong Dang for a great and fun time together and a productive work atmosphere. Particularly, I would like to thank Bernadette for her advice on this thesis. I would like to thank Dr. Lucy Brunt, Lauren Porter, Simone Schindler and Jenna Corcoran for an amazing last period of my PhD in Exeter and for both helpful discussions and physical balance. I would like to thank my collaboration partners. I would like to thank Prof. Suat Özbek and Dr. Lilian Kaufmann for the intriguing insight into the Xenopus model, Prof. Ulrich Nienhaus and Dr. Benedikt Prunsche for FCS support, and Prof. David Virshup and Dr. Gediminas Greicius for their remarkable organoid addition. I would like to express a special gratitude to my parents, all my friends, and especially my wife Daniela, who gave me the strength and endurance I needed to always continue and accomplish this work. IX List of publications Mattes, B., Y. Dang, G. Greicius, L.T. Kaufmann, B. Prunsche, J. Rosenbauer, J. Stegmaier, R. Mikut, S. Özbek, G.U. Nienhaus, A. Schug, D.M. Virshup, and S. Scholpp. 2018. Wnt/PCP controls spreading of Wnt/β-catenin signals by cytonemes in vertebrates. Elife. 7:1–28. Brinkmann, E.M., B. Mattes, R. Kumar, A.I.H. Hagemann, D. Gradl, S. Scholpp, H. Steinbeisser, L.T. Kaufmann, and S. Özbek. 2016. Secreted Frizzled-related Protein 2 (sFRP2) redirects non-canonical Wnt signaling from Fz7 to Ror2 during vertebrate gastrulation. J. Biol. Chem. 291:13730–13742. Stanganello, E., A.I.H. Hagemann, B. Mattes, C. Sinner, D. Meyen, S. Weber, A. Schug, E. Raz, and S. Scholpp. 2015. Filopodia-based Wnt transport during vertebrate tissue patterning. Nat. Commun. 6:5846. Mattes, B., S. Weber, J. Peres, Q. Chen, G. Davidson, C. Houart, and S. Scholpp. 2012. Wnt3 and Wnt3a are required for induction of the mid-diencephalic organizer in the caudal forebrain. Neural Dev. 7:12. Mattes B, Scholpp S. Emerging role of contact-mediated cell communication in tissue development and diseases. The manuscript has been submitted to Histochemistry and Cell Biology. Rosenbauer J, Mattes B, Reinartz I, Wedgwood K, Schindler S, Sinner C, Scholpp S, Schug A. Modeling of Wnt-mediated Tissue Patterning in Vertebrate Embryogenesis The manuscript has been submitted to PNAS. X Table of Contents ABSTRACT ....................................................................................................................................... VII ACKNOWLEDGEMENTS ...............................................................................................................IX LIST OF PUBLICATIONS ................................................................................................................ X TABLE OF CONTENTS ..................................................................................................................XI FIGURE INDEX .............................................................................................................................. XIV ABBREVIATIONS .......................................................................................................................... XVI 1. INTRODUCTION ........................................................................................................................ 1 1.1. DEVELOPMENT OF MULTICELLULAR ORGANISMS ............................................................. 1 1.2. ROLE OF MORPHOGENS DURING DEVELOPMENT ............................................................... 1 1.3. MORPHOGENS ORIGINATE FROM LOCAL ORGANIZING CENTERS ....................................... 3 1.4. THE WNT SIGNALING PATHWAY ....................................................................................... 5 1.4.1. Wnt signaling in development and disease ............................................................... 5 1.4.2. Molecular mechanism of Wnt signal transduction ................................................... 7 1.4.3. Canonical Wnt/β-catenin pathway ........................................................................... 8 1.4.4. The Wnt/ß-catenin pathway during neural plate pattern formation ....................... 10 1.4.5. Non-canonical β-catenin independent pathway ..................................................... 12 1.5. ROR-FAMILY RECEPTOR TYROSINE KINASES ................................................................... 15 1.5.1. Domain architecture ............................................................................................... 15 1.5.2. Ror-family RTKs in development ............................................................................ 16 1.5.3. Ror2 function as a Wnt receptor and its role in Wnt signal transduction .............. 17 1.6. WNT PROTEINS: STRUCTURE, MATURATION AND SECRETION ........................................ 19 1.7. ACTIVE DISTRIBUTION MECHANISMS OF WNT MOLECULES ............................................ 22 1.7.1. Restricted diffusion by HSPGs ............................................................................... 23 1.7.2. Free diffusion facilitated by Wnt binding proteins ................................................. 24 1.7.3. Exovesicles as morphogen carrier ........................................................................
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