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Progenitor Cell Mechanisms Contributing to Cortical Malformations : Studying the Role of the Heterotopia Gene Eml1/EML1 in Radial Glia Ana Uzquiano Lopez

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Progenitor Cell Mechanisms Contributing to Cortical Malformations : Studying the Role of the Heterotopia Gene Eml1/EML1 in Radial Glia Ana Uzquiano Lopez Progenitor cell mechanisms contributing to cortical malformations : studying the role of the heterotopia gene Eml1/EML1 in radial glia Ana Uzquiano Lopez To cite this version: Ana Uzquiano Lopez. Progenitor cell mechanisms contributing to cortical malformations : studying the role of the heterotopia gene Eml1/EML1 in radial glia. Human genetics. Sorbonne Université, 2019. English. NNT : 2019SORUS392. tel-03241793 HAL Id: tel-03241793 https://tel.archives-ouvertes.fr/tel-03241793 Submitted on 29 May 2021 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. Sorbonne Université Ecole Doctorale ‘Complexité du Vivant’ ED515 Institut du Fer à Moulin / Cortical Development and Pathology Progenitor cell mechanisms contributing to cortical malformations: studying the role of the heterotopia gene Eml1/EML1 in radial glia. Ana UZQUIANO LÓPEZ Thèse de doctorat de Génétique et Neurodéveloppement Dirigée par Fiona FRANCIS Présentée et soutenue publiquement le 27 Mai 2019 Devant un jury composé de : - SPASSKY, Nathalie, Research Director, Institut de Biologie de l’Ecole Normale Superior, UMR 8197, Paris, France (Président). - HUTTNER, Wieland, Professor, Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany (Rapporteur). - REPRESA, Alfonso, Research Director, Institut de Neurobiologie de la Méditerranée, Marseille, France (Rapporteur). - MARTHIENS, Véronique, Researcher, Institut Curie, UMR 144, Paris, France (Examinateur). - BORRELL, Victor, Principal Investigator, Instituto de Neurociencias de Alicante, San Juan de Alicante, Spain (Examinateur). - FRANCIS, Fiona, Research Director, Institut du Fer à Moulin, UMR-S 1270, Paris, France (Directeur de thèse). A mis padres, Trini y Juanjo I Acknowledgements I thank my PhD director, Fiona. Thank you for welcoming me in your lab. Thank you for your trust, your support and for always encouraging me to go one step further. Thank you for your help in the difficult moments but also for the great discussions and input throughout all these years. I have learnt a lot with you and from you. Thank you Sara, Delfina and Melissa. Sara, it was a real pleasure to ‘share’ project with you. Delfina, with our ups and downs, I feel lucky I got to live this experience with you by my side. We have learnt many things together, and we have also laughed about many things together. Melissa, thank you for having always been there. For being always available to discuss anything: from confocal imaging to Golgi cisternae and trafficking. But most of all, thank you for always boosting me; for not always telling me what I wanted to hear, but always with the best of your intentions and the purest honesty. Thank you. Marika, working with you makes the lab a brighter place. Thank you for your help with scientific discussions and French corrections, but moreover, thank you for sharing and caring. I also thank all other members of the team: Laurence, Marta, Giorgia, Maxime, Richard Gael and Anne for all the discussions and the good time spent together. Special thanks to Anne, for her great involvement in my project. Thanks to my good friends in the IFM who were always there to share this experience: Ferran, Jimmy, Maria and Melanie. You have all in your way helped me throughout these years: from sharing the first experiments, to leaving notes all over my desk to encourage me through my thesis writing. Jimmy, thank you for the many hugs and for being the chosen family while in Paris. I thank Victor Borrell and his lab for welcoming me in Alicante. Cristina, gracias por las risas, las discusiones y los infinitos audios. I thank the rest of my good ‘Parisian’ friends; Sebastian and Estefani, thank you for sharing frustrations over drinks and nice dinners. Elise and Robin, thank you for your generosity: spending time with you is a bit like being home. Gracias a todos mis amigos de fuera que me han apoyado desde fuera, siempre interesados por mi día a día, por mi proyecto presente pero también por los futuros. Gracias por las visitas y por poquito a poquito hacer de la distancia algo relativo. María, Paloma A., Donais, Robert, Sofía, Laura, Silvia, Mario, Gonzalo, Mónica, Álvaro G. y Álvaro B., gracias. Un gracias inmenso a Sundary y Paloma. Sundary, hemos compartido esto de principio a fin, y has sido una II compañera de camino espectacular. Gracias por escuchar y aconsejarme sobre el más mínimo problema, y gracias por recordarme que a veces es bueno parar y descansar. Gracias por vivir mis alegrías de una forma tan cercana. Paloma, gracias por el apoyo, por ir entendiendo mi rutina poco a poco, por estar tan cerca estando a muchos kilómetros, por la disponibilidad absoluta cada vez que volvía a casa. Gracias a Iñigo Azcoitia, mi profesor de Desarrollo y Plasticidad del Sistema Nervioso durante mi carrera. Gracias por guiarme en mis primeros pasos y no dejar que tirara la toalla nunca. Gracias a mi familia, especialmente a mis tíos Pili y Jorge, y a mis primos Javi, Lola, Jorge y Julia. También a las pequeñas Silvia y Alicia. Gracias por los reencuentros y por el cariño, por el interés y por aprovechar de las ocasiones que tenemos para estar juntos. Pasar tiempo con vosotros ha sido siempre coger energía y llenarme de luz. Papá y mamá, sin vosotros hacer una tesis no hubiera sido posible. Primero, gracias por educarme como ‘una mujer del siglo XXI’, no ponerme nunca frenos y confiar en que haría aquello que me propusiera. Gracias por dejarme volar, por adaptaros a mi ritmo (a veces frenético) y disfrutar conmigo de mis aventuras, ya sean en Madrid, Londres, Paris, o ahora Boston. Gracias por ayudarme con mudanzas, médicos, comidas y demás cosas ‘simples’ del día a día a pesar de la distancia. Gracias por los innumerables viajes. Vuestra ayuda siempre hace el camino más ligero. Gracias por seguir mi trabajo, mis viajes a conferencias, mis presentaciones, y por alegraros de cada una de mis pequeñas victorias como si fueran vuestras. Gracias por ser el soporte más estable y seguro. Finalmente, gracias Pietro. Creo que una tesis la hace contigo quien esta día tras día, incluyendo noches de pesadillas, días muy largos de trabajo, fines de semanas delante del ordenador y muchos viajes fuera de casa. Tú has estado siempre. Gracias por compartir estos años conmigo, por escuchar mis presentaciones hasta la saciedad, ayudarme con tests estadísticos y preocuparte por la polaridad de mis progenitores tanto como yo. Gracias por ser casa, y por ser calma y tranquilidad. III Table of contents Aknowledgments ........................................................................................................................ II Table of contents ....................................................................................................................... IV List of figures ............................................................................................................................ VII Introduction ............................................................................................................................... 1 Preamble .................................................................................................................................... 2 1. From neuroectoderm to dorsal telencephalon: early events of central nervous sytem development .......................................................................................................................... 3 2. The cerebral cortex ........................................................................................................ 6 2.1 The cortical lobes and areas .................................................................................... 6 2.2 Evolutionary considerations: neocortex and allocortex .......................................... 8 2.3 Cellular diversity in the neocortex ........................................................................... 8 2.3.1 Glia .................................................................................................................... 8 2.3.2 Projection neurons and interneurons .............................................................. 9 3. Cortical development: neural progenitor diversity and neuronal production ............ 12 3.1 Progenitor cell types (adapted from Uzquiano et al., 2018) ................................. 13 3.1.1 Apical progenitor: neuroepithelial cells (NEs) and apical radial glial cells (aRGs)…......................................................................................................................... 13 3.1.2 Basal progenitors (BPs): intermediate progenitors (IPs) and basal radial glial- like cells (bRGs) and their implication in cortical expansion ........................................ 16 3.2 Apical radial glial cells: key features mediating their behavior (adapted from Uzquiano et al., 2018) ...................................................................................................... 22 3.2.1 Cell cycle length considerations…. ................................................................. 23 3.2.2 Polarity complex and
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