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Caractérisation Fonctionnelle De La Protéine ANKS3 Impliquée Dans Les Ciliopathies Rénales Et Étude De Son Rôle Dans La Régulation Des Arns Gweltas Odye

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Caractérisation Fonctionnelle De La Protéine ANKS3 Impliquée Dans Les Ciliopathies Rénales Et Étude De Son Rôle Dans La Régulation Des Arns Gweltas Odye Caractérisation fonctionnelle de la protéine ANKS3 impliquée dans les ciliopathies rénales et étude de son rôle dans la régulation des ARNs Gweltas Odye To cite this version: Gweltas Odye. Caractérisation fonctionnelle de la protéine ANKS3 impliquée dans les ciliopathies rénales et étude de son rôle dans la régulation des ARNs. Biologie cellulaire. Université Sorbonne Paris Cité, 2018. Français. NNT : 2018USPCB029. tel-02490646 HAL Id: tel-02490646 https://tel.archives-ouvertes.fr/tel-02490646 Submitted on 25 Feb 2020 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 PARIS DESCARTES Ecole doctorale Bio Sorbonne Paris Cité Département Biologie Cellulaire et Moléculaire, Physiologie, Physiopathologie (BCMPP) Gweltas ODYE Pour l’obtention du grade de Docteur en Sciences Sujet : Caractérisation fonctionnelle de la protéine ANKS3 impliquée dans les ciliopathies rénales et étude de son rôle dans la régulation des ARNs Soutenue le 2 Juillet 2018 Composition du Jury Dr. Jeanne AMIEL Dr. Bénédicte DURAND Dr. Brigitte LELONGT Dr. Hervé LE HIR Dr. Philippe BASTIN Dr. Sophie SAUNIER Les lois de la science ne distinguent pas le passé du futur. Stephen Hawking REMERCIEMENTS 1 | P a g e 2 | P a g e REMERCIEMENTS 1310 jours, 333 Western Blots, 2610 Heures de microscopie, 102 qPCR, plus de 50 000 cils analysés et un papier plus tard, le temps est venu de refermer ce chapitre. Evidemment tout ceci n’aurait jamais été possible sans apprendre, sans aide ou sans soutien. Je vais donc ouvrir cette thèse par quelques remerciements. Je tiens d’abord à remercier Sophie qui m’a donné l’occasion de réaliser mon stage de M2 dans son laboratoire et de poursuivre par ma thèse. Merci +++ d’avoir cru que je pouvais le faire et de m’avoir permis d’avoir ce financement. Merci de m’avoir tant appris sur la science mais aussi sur moi-même. Ca n’aura pas été facile tous les jours mais on retiendra le meilleur L’un n’allant pas sans l’autre, je tiens aussi à remercier Alex et Cécile. Merci pour toutes ces discussions, scientifiques ou non. Merci également d’avoir su arrondir les angles quand il le fallait. Ensuite je veux remercier ma famille, même si à l’évidence les mots ne sont pas suffisants pour exprimer ce que je pense. Mes parents, mon frère et ma sœur, ma grand-mère et mon parrain sans qui tout cela ne se serait jamais produit, sans qui aujourd’hui je ne serais ni là où je suis, ni qui je suis. Votre soutien pendant ces 4 voire 5 années a été inébranlable, y compris dans les pires moments, alors MERCI. Et il y’à toi, toi qui partageais ma vie au labo et toujours en dehors. Merci de me supporter (et on sait tous à quel point c’est difficile) dans tous les sens du terme. Merci d’avoir su me pousser et me trainer au labo quand il le fallait mais aussi m’apaiser quand j’en avais besoin. Cette thèse est importante pour moi et je n’aurais jamais réussi à la finir si tu n’avais pas accepté les week-ends au labo, les horaires pas possibles, et autres séances d’écriture/relecture interminables. En parlant de famille, je veux remercier ma seconde famille, celle avec qui j’ai passé la majorité de mon temps durant cette thèse, je parle de celle du labo. Je tiens à préciser qu’il existe à l’évidence une hiérarchie dans ces remerciements, je vous laisse la trouver. Tout d’abord, Flora, merci de m’avoir formé à mon arrivée, de m’avoir soutenu et fait croire en moi, ce sont des choses dont je me rappellerai à vie. Et il y’a Christelle. Je pourrais en écrire des pages, mais je te remercierai juste pour toutes ces discussions (souvent non scientifique), pour tes e-mails enflammés, et évidemment pour ta bonne humeur « petite tête de linotte ». Je pense à Corinne pour toutes les discussions dominicales à propos d’à peu près tout, c’était un vrai plaisir. Merci à Gégé, tu as été la plus grande cause de mon taux de caféine dans le sang. Merci aussi Olivier, pour les discussions sur le sport, pour avoir solutionné plus d’un problème et finalement pour la dose de testostérone quotidienne, y’en avait bien besoin dans 3 | P a g e REMERCIEMENTS ce labo. En parlant de testostérone, comment ne pas penser à Maxence ? Mon p’tit pote, on s’est serré les coudes dans les moments difficiles et on a fêté les (nombreux) bons moments. Je crois en toi. Merci à Guillaume et Hugo pour les interludes d’enquêtes policières et les bons moments passés ensemble. Merci à Marion avec qui j’ai partagé ce travail, tu m’as beaucoup appris. Merci à Meriem pour sa bonne humeur et pour les crénaux arrangés en sous mains. Loulou et Lala, vous êtes indissociable ce fut un plaisir de partager tous ces bons moments avec vous et merci pour le soutien incroyable dont vous avez fait preuve pendant la redaction….et les corrections…. (non on ne parlera pas de semi marathon ici). Merci à Evelyne pour m’avoir fait me sentir normal et merci Camille pour les mois de juin tennistique et pour ton rire communicatif. Laurine, tes mails me manqueront toujours et Gaelle j’espère avoir l’occasion de t’entendre mixer à nouveau. Albane, tu as un peu été un mentor pour moi, mais aussi une amie (et evidemment la meilleure, la plus sympa, la plus belle et la plus intelligente, mon modèle dans la vie). Merci de m’avoir fait découvrir la culture Albanaise et ta passion pour cet art qu’est la collection de cheveux. Je ne remercierai pas Esther et tu sais pourquoi. Sarach, au début je te voyais comme une brute, aujourd’hui c’est toujours le cas, mais merci quand même. Marie et Daniel je vous mets ensemble, vous savez pourquoi ce fut un plaisir de rencontrer d’aussi grands humoristes. Je pense aussi aux autres équipes, « aux Simons » particulièrement à Julie, Zvoni et Maria et « aux Gourdon » notamment à Elodie, Sandra et évidemment Mario, tu as rendu mes gels BET bien plus drôle. Bien sûr je n’ai pas oublié mes colocataires de bureau, je pense à Rebecc et à Frances. J’ai tellement partagé avec vous. Pas facile de me supporter à longueur de journée, pas facile de vous supporter à longueur de journée, je pense que l’on faisait un trio parfait ! Merci aussi à Vale, « Team Nature » comme tu disais. Tu m’as accueilli à bras ouverts (ou à tentacules ouvertes comme tu veux Polpo) quand je suis arrivé et tu es devenue une vraie amie. Alors merci d’avoir cru en moi, de m’avoir fait confiance, de m’avoir soutenu et de m’avoir appris à parler parfaitement italien. Merci également à Alix et Romain pour tout, des discussions scientifiques aux soirées en passant par les conférences de biologie cellulaire à Curie evidemment. Enfin j’ai une pensée pour la « bande du fond » aujourd’hui tous docteurs, vous auriez pu m’attendre quand même. En fin, j'aimerais remercier le jury, Brigitte LELONGT, Bénédicte DURAND, Hervé LE HIR, Philippe BASTIN et Jeanne AMIEL et qui ont accepté d'évaluer mon travail. 4 | P a g e RESUME 5 | P a g e 6 | P a g e RESUME Caractérisation fonctionnelle de la protéine ANKS3 impliquée dans les ciliopathies rénales et étude de son rôle dans la régulation des ARNs La néphronophtise (NPH) est une néphropathie tubulo-interstitielle autosomique récessive, caractérisée par la présence d'une fibrose interstitielle massive et la formation de kystes. Elle est une cause majeure d'insuffisance rénale terminale chez l'enfant ou le jeune adulte. Elle peut être isolée ou associée à des atteintes extrarénales. La NPH appartient au groupe des ciliopathies, un ensemble de maladies multisystémiques causées par des mutations dans des gènes codant des protéines participant à la fonction des cils primaires et motiles. Le cil primaire agit, à la surface de la plupart des cellules, comme un mécano et chimiosenseur contrôlant des voies de signalisation essentielles au développement et à l'homéostasie tissulaire (Sonic hedgehog (Shh), Wnt, polycystines/Calcium, mTOR). La NPH est une maladie génétiquement hétérogène, avec vingt-trois gènes NPHP responsables identifiés à ce jour (dont 14 dans notre laboratoire). La plupart de ces gènes codent des protéines assurant des fonctions ciliaires telles que le contrôle de la composition protéique et de la signalisation ciliaire, à la base du cil (zone de transition (TZ)), au niveau du compartiment Inversine (CI), ou lors du transport intraflagellaire (IFT). Par analyse d’exome, nous avons identifié une mutation homozygote pathogène dans un nouveau gène, ANKS3, responsable d'une NPH associée à une fibrose hépatique. ANKS3 code une protéine à domaines Ankyrines et SAM, connue pour interagir avec plusieurs protéines NPHP de la TZ (NPHP1), du CI (ANKS6, NEK8) ainsi qu'avec BICC1, une ribonucléoprotéine mutée dans les dysplasies rénales kystiques. Mon projet de thèse a porté sur la caractérisation de la fonction d'ANKS3 et de l'impact de la mutation humaine dans les processus cellulaires altérés dans les ciliopathies rénales.
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