Role of the Glycogen Synthase Kinase 3 for the Retinal Development and Homeostasis François Paquet-Durand To cite this version: François Paquet-Durand. Role of the Glycogen Synthase Kinase 3 for the Retinal Development and Homeostasis. Neurobiology. Université Paris Saclay (COmUE), 2018. English. NNT : 2018SACLS060. tel-01751427 HAL Id: tel-01751427 https://tel.archives-ouvertes.fr/tel-01751427 Submitted on 29 Mar 2018 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. Role of the Glycogen Synthase Kinase 3 in Retinal Development and Homeostasis Rôle de la Glycogène Synthase Kinase 3 dans le Développement et l'Homéostasie de la Rétine : 2018SACLS060 : 2018SACLS060 NNT Thèse de doctorat de l'Université Paris-Saclay préparée à l’Institut des Neurosciences Paris-Saclay UMR9197 École doctorale n°568 BIOSIGNE Spécialité de doctorat: Sciences de la vie et de la santé Thèse présentée et soutenue à Orsay, le 22 mars 2018, par Elena Braginskaja Composition du Jury: Pr. Simon Saule Président Pr. François Paquet-Durand Rapporteur Pr. Thomas Lamonerie Rapporteur Dr. Marie-Paule Felder-Schmittbuhl Examinatrice Dr. Gaël Orieux Examinateur Dr. Muriel Perron Directrice de thèse Dr. Jérôme Roger Co-Directeur de thèse To My Parents, To Lutz Neumann ACKNOWLEDGEMENTS My 4-year adventure in France comes to the end with the accomplishment of my Ph.D. studies. Before heading for an “old-new life” in my home country, I would like to thank all the people, who accompanied and supported me in my journey that started with the Erasmus exchange in 2014, followed by my Master internship and finally my Ph.D. thesis. I would like to start by expressing my gratitude to my thesis director Muriel Perron. Thank you so much for the scientific growth I experienced through all the years on your team: First during my Erasmus internship, then during my Master internship and the Ph.D. thesis. I am very grateful to you for all your support and guidance and I appreciate the time you dedicated to improving my manuscript. Especially, I would like to deeply thank my thesis director Jérôme Roger. First, for the great opportunity and trust to work on this project during my Master internship and then continuing on Ph.D. thesis. Thank you for providing me with invaluable guidance, constructive feedback and supporting me at each stage of my work and beyond, even when it was the hardest. Thank you for the time dedicated to correcting my manuscript. Finally, I hope that our hard work could reward us with fruitful results in the (very) near future. I wish to acknowledge Pr. Simon Saule for the honour of presiding my Jury. I would like to thank Pr. François Paquet-Durand and Pr. Thomas Lamonerie for accepting to evaluate my work as well as Dr. Marie-Paule Felder-Schmittbuhl and Dr. Gaël Orieux who have accepted to be my examinators. Furthermore, I am grateful to Dr. Célio Pouponnot and Dr. Thierry Léveillard for having evaluated my work during my mid-term examination and to Dr. Thierry Léveillard for the tutorship of my Ph.D. work. I would like to thank the all the team of the Ernst Ludwig Ehrlich Studienwerk, and especially Dr. Eva Lezzi and Pr. Vingron for all the support and regular exchange during the past years, and for all the seminars, workshops and meetings. Furthermore, I would like to thank ELES for the financial support that allowed me to continue my Ph.D. I would also like to thank the Studienstiftung des deutschen Volkes, in particular the Max-Weber Program Bayern for sponsoring seminars as well as scientific and linguistic workshops and summer schools during my Master and Ph.D. studies. A particular thought to all the great people I had the chance to meet and with whom I exchanged through these events. I would like to thank the team of Pierre-Marie Lledo, and notably Françoise and Marie with whom I accomplished my second Erasmus internship. Thank you for the great exchange and everything I could learn from you. I am grateful to all the people in the animal facility at Gif for taking care of the animals, and in particular Krystel, Valérie and Xavier. Also, I am thankful to our “neighbors”: Vero, Sandrine, Jean-Vianney, Kevin and Nathalie for their availability and kindness. I would like to express my gratitude to our collaborators, members of Anand Swaroop’s lab at the NIH in the US lab. Thank you particularly for welcoming me in such a friendly atmosphere in the US during the ARVO conference 2017. Furthermore, I thank Robin from Alain Chédotal lab at the Vision Institute for our fruitful collaboration on one of my projects. I II I deeply thank all members of the CERTO and SCaNR team for great teamwork, for help and discussion and a friendly atmosphere. More personally, I would like to thank Odile for her friendliness and valuable advice during the meetings and Morgane for our discussions on the way to the lab as well as for all the valuable advice. I profoundly thank Tatiana for always being there when needed, for our long discussions in Russian and all for all her encouragements. Of course, I would like to express my gratitude to Christel. Thank you for being kind and supportive at all times. I am grateful to Karine, my closest neighbor in our office Thank you for our agreeable discussions, and your friendliness and support! I thank Sophie for her support with experiments, but also for her kindness and our nice discussions. I thank Elodie for her help, and in particular during my Master internship and my first Ph.D. year. I appreciated our agreeable discussions during the ERG experiment. I thank Alicia for always being joyful and smiling, Diana (although you could talk a little bit slower in Spanish for me ) and Divya. Expressly, I wish to say a big “thank you” to Annaïg and Juliette. Annaïg, my «forerunner», thank you for everything, all the support, but also the fun we had during the years. I would explicitly like to mention your active participation in my journey of MT180 . And Juliette, certainly I thank you for all the valuable scientific advice and guidance (thank you for having taught me many molecular and cellular biology methods), but especially for your constant encouragements and your enormous support in most, if not all, difficult situations and moments I experienced! Another big “thank you” I would like to express to the “other” men in our lab: Albert and Rodrigo Albert, thank you for being so easy-going, supportive and amicable! Thank you for your friendship and our discussions inside and outside the lab. Rodrigo, thank you for all the support and for simply being there, my friend! Furthermore, I thank Rahul, who has already left the lab, with whom my journey started on the 31st March 2014, for managing the obstacles, but also for sharing plenty of good moments together. Finally, I would like to thank all the students who were doing their internship with me during my Master and Ph.D.: Megan, Claire, Nareh, Louise, Alexana and Leah, but also Elise who came during the last month of my Ph.D. In particular, my friend Louise for her support during her (unfortunately) short stay in the lab, and Megan, Leah and Elise for their help with English. III IV My acknowledgements would not be complete without mentioning all my wonderful and very international family members and friends. I warmly thank all my friends I found in France. In particular, my very first friend, Benoît for having discovered Paris with me and for still keeping in touch. Guillaume, my faithful friend, for all our adventures in France and abroad. Koen for our German-Dutch exchange and the fun in the polyglot club that facilitated me my last weeks of work on this manuscript . Giovanni and Tito, my “big brothers” in France, true friends and supporters during the years, who are always there. Furthermore, I thank all my other friends spread all across the globe for keeping in touch! I deeply thank my family, my dearest parents, my brother Ilia, his wife Oksana as well as my niece Veronika and my nephew Netanel for their unwavering love and support despite the great distance between us. I thank all my other family members, most of whom are (very) far, for the regular contact and constant support! And Steven. Thank you for all the joy you bring to my life and everything to come! Last but not least (and the most important comes at the end) I would like to express my immense gratitude to Lutz, my pillar, my friend, my everything. Words are not enough to describe my gratitude to you. It is to you that I dedicate my thesis. V VI Contents A Résumé détaillé ........................................................................................................ 3 B Introduction ............................................................................................................... 9 B.1 Visual perception ................................................................................................. 9 B.1.1 Anatomy of the eye ....................................................................................... 9 B.1.2 Organization of the retina.............................................................................. 9 B.2 Retinal dystrophies and available treatments ..................................................... 21 B.2.1 Photoreceptor dystrophies .......................................................................... 21 B.2.2 Available treatments ................................................................................... 27 B.3 Development of the vertebrate retina ................................................................. 33 B.3.1 Retinal specification .................................................................................... 33 B.3.2 Retinal proliferation maintenance of progenitors ........................................