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Systematic Assessment of the Role of Dynein Regulators in Oriented Cell

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Systematic Assessment of the Role of Dynein Regulators in Oriented Cell Systematic assessment of the role of Dynein regulators in oriented cell divisions by live RNAi screen in a novel vertebrate model of spindle orientation Maria Florencia Di Pietro To cite this version: Maria Florencia Di Pietro. Systematic assessment of the role of Dynein regulators in oriented cell divisions by live RNAi screen in a novel vertebrate model of spindle orientation. Cellular Biology. Université Pierre et Marie Curie - Paris VI, 2016. English. NNT : 2016PA066405. tel-01592476 HAL Id: tel-01592476 https://tel.archives-ouvertes.fr/tel-01592476 Submitted on 25 Sep 2017 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. Systematic assessment of the role of Dynein regulators in oriented cell divisions by live RNAi screen in a novel vertebrate model of spindle orientation Maria Florencia di Pietro PhD thesis Université Pierre et Marie Curie Ecole doctorale Complexité du Vivant Institut de Biologie de l’Ecole Normale Supérieure, Team: « Cell division and Neurogenesis » Systematic assessment of the role of Dynein regulators in oriented cell divisions by live RNAi screen in a novel vertebrate model of spindle orientation Par Maria Florencia di Pietro Thèse de doctorat de Biologie Cellulaire Dirigée par Dr Xavier Morin Présentée et soutenue publiquement le 23 Septembre 2016 Devant un jury composé de : Gho, Michel- Research Director- Président du Jury Gotta, Monica- Professor- Rapportrice Mapelli, Marina- Research Director- Rapportrice Bellaiche, Yohanns-Research Director- Examinateur ACKNOWLEDGEMENTS First of all I want to thank Xavier for welcoming me in his lab and for being an excellent thesis supervisor during all these years. I would like to thank him for the guidance and support during my project, for allowing me to discover the world of cell biology and imaging, and for being also great at the human level. I also want to thank him for trusting me by proposing a huge and ambitious project, for his great contribution to my development as a young researcher and for always proposing solutions and saying the right things at the right moment. Secondly I want to thank my favorite postdocs, Mehdi and Samuel, for being invaluable colleagues, for sharing with me their experience, for sharing great conversations about science life and life in science. Each of you has enormously contributed to my PhD years in a different manner and I have greatly appreciated having you as colleagues since I joined the lab; you have been awesome. I want to thank our technicians in the lab for helping me with cell cultures. Raphael, a former technician in the lab, for accompanying me in my first steps in the cell culture room. Rosette, our current technician, for having helped me by maintaining cell lines and assisting me in preparing materials all along these years, and for being a really nice colleague. Next I want to thank Chooyoung and Evelyne, too more recently incorporated members of the lab, for being great colleagues in everyday life lab and for helping and being kind with me. I have really spent great times in Xavier’s lab, which I consider a treasure in my career and more generally in life. Thank all of you for creating this amazing atmosphere I could find both at the scientific and human level. Moreover, I want to thank different people who I worked with especially during the first years. Léo, for having spent very nice times working together, and for his feedback, his interest and collaboration on my project. Simon, for our interesting collaboration working in optogenetics and for further help with other aspects of my project. More generally, I would like to thank all the 0 “optoclubbers”, for our meetings about optogenetics and cell division orientation, and also because we’ve had a lot of fun together. In addition, I thank a lot to Auguste Genovesio, Yingbo Li and France Rose for collaborating on my project by developing software for data analysis. Furthermore I thank all the people of the imaging platform of the institute for assistance during these years. I also want to thank the people from 7th floor of the IBENS for being nice and helpful these years. More generally, thanks to the people that have contributed with protocols, reagents, cell lines or in other aspects of my project: Olivier Collin, Nicolas Carpi and Matthieu Piel, Salah Elias, Mickael Machicoane and Arnaud Echard, Iain Cheeseman, the Hyman lab and Maria Bagonis. Moreover, I would like to thank Monica Gotta, Marina Mapelli, Yohanns Bellaiche and Michel Gho for accepting to participate as a jury of my thesis. Also many thanks to the members of my thesis committee, Renata Basto, Marie-Emilie Terret and Matthieu Piel, for the excellent input to my project during our two meetings. I also want to mention great people I have known in Paris: the friends I have made at Cité U, my mates from M2, my “more Parisian” friends, people from the theater classes and every other nice person that I have met along my way. Thank you all for nice moments spent together. Thanks also to my friends from life in Buenos Aires, for supporting me and for keeping in touch all these years. Finally I want to thank my brother, my sister and my parents who, while being 11k km far away from me, have unconditionally supported me in every aspect of life during all these years. Thanks Euge and Fede for always being there for me. Thanks Mum and Dad for adapting so well to the distance, for helping me with everything and for visiting me every year. These years would not have been the same without the support of my family. 1 CONTENTS Acknowledgements .......................................................................................................................................... 0 Figures index .................................................................................................................................................... 7 Glossary ............................................................................................................................................................ 8 Abstract .......................................................................................................................................................... 10 Résumé .......................................................................................................................................................... 12 Chapter 1: Mitotic spindle orientation in development and disease ................................................................. 14 1-1 Generation of cellular diversity .............................................................................................................. 14 1.1.1- Drosophila Neuroblasts ................................................................................................................. 17 1.1.2- Mouse Skin progenitors ................................................................................................................. 19 1.1.3- Vertebrate neural progenitors ....................................................................................................... 20 1.2. Morphogenetic processes..................................................................................................................... 24 1.3-Tumorigenesis....................................................................................................................................... 28 1.3.1- Deregulation of stem cells compartments ...................................................................................... 28 1.3.2- Epithelial disruption ....................................................................................................................... 29 1.4. Conclusion ........................................................................................................................................... 31 Chapter 2: Mechanisms of mitotic spindle orientation ..................................................................................... 33 2.1. Introduction ......................................................................................................................................... 33 2.2- The LGN complex ................................................................................................................................. 34 2.3. Models for studying spindle orientation................................................................................................ 38 2.4. New insights into the molecular regulation of LGN complex recruitment/stability at the cortex ............ 40 2.4.1. Molecules regulating the recruitment /stability of the LGN complex at the cortex .......................... 40 2.4.2. Temporal and spatial regulation of LGN complex localization ......................................................... 43 2.4.3. Not a monopoly: Gαi/LGN independent pathways in spindle orientation ........................................ 49 2.5- The emerging role of actin in spindle orientation .................................................................................. 51 2.5.1. Requirement of an intact
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