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Ce Document Est Le Fruit D'un Long Travail Approuvé Par Le Jury De Soutenance Et Mis À Disposition De L'ensemble De La Communauté Universitaire Élargie AVERTISSEMENT Ce document est le fruit d'un long travail approuvé par le jury de soutenance et mis à disposition de l'ensemble de la communauté universitaire élargie. Il est soumis à la propriété intellectuelle de l'auteur. Ceci implique une obligation de citation et de référencement lors de l’utilisation de ce document. D'autre part, toute contrefaçon, plagiat, reproduction illicite encourt une poursuite pénale. Contact : [email protected] LIENS Code de la Propriété Intellectuelle. articles L 122. 4 Code de la Propriété Intellectuelle. articles L 335.2- L 335.10 http://www.cfcopies.com/V2/leg/leg_droi.php http://www.culture.gouv.fr/culture/infos-pratiques/droits/protection.htm Ecole Doctorale BioSE (Biologie-Santé-Environnement) Thèse Présentée et soutenue publiquement pour l’obtention du titre de DOCTEUR DE l’UNIVERSITE DE LORRAINE Mention : « Sciences de la Vie et de la Santé » Par Andréa GEOFFROY Conséquences d’une carence en donneurs de méthyles sur la différenciation neuronale et la plasticité : influence d’une supplémentation périnatale sur le développement cérébral. Le 08 Septembre 2015 Membres du jury : Rapporteurs : Pr. Marie-Laure Kottler PU-PH, U1075 INSERM, Caen, France Dr. Patrick Anglard DR, U7364 CNRS, Strasbourg, France Examinateurs : Dr. Hervé Moine DR, CNRS 7104 / INSERM U964, Strasbourg, France Pr. Jean-Louis Guéant PU-PH, U954 INSERM, Nancy, France Dr. Jean-Luc Daval DR, U954 INSERM, Nancy, France Directeur de thèse Dr. Carine Bossenmeyer-Pourié MCU, U954 INSERM, Nancy, France, Co-directeur de thèse Membres invités: Pr. Bruno Charpentier PR, U7365 CNRS, Nancy, France _________________________________________________________________________________ UMR 954 INSERM – «Nutrition, génétique et exposition aux risques environnementaux» 9 avenue de la Forêt de Haye-Faculté de Médecine - 54500 Vandoeuvre-lès-Nancy REMERCIEMENTS Je transmets mes sincères remerciements : A Madame le Professeur Marie-Laure Kottler et à Monsieur le Docteur Patrick Anglard pour avoir accepté d’être rapporteurs pour ma soutenance de thèse. Merci pour le temps et l’intérêt que vous avez porté à l’évaluation de ce travail. A Monsieur le Docteur Hervé Moine, d’avoir accepté d’être examinateur. Une page se tourne et de nouveaux horizons s’ouvrent au sein de votre équipe. J’espère que le post- doctorat sera riche en contribution dans le domaine du X-Fragile. A Monsieur le Professeur Bruno Charpentier pour avoir participé à l’évaluation et au suivi de ce travail, en tant que membre du comité de suivi de thèse. A Monsieur le Professeur Jean-Louis Guéant, directeur du laboratoire, de m’avoir accueilli au laboratoire INSERM U954 NGERE pour ces quelques années de recherche, dans le cadre du Master et de la Thèse. Pour m’avoir permis d’intégrer un établissement où la chaleur humaine est grande et où les compétences sont nombreuses ; me permettant la mise en œuvre de ce projet. C’est d’abord grâce à vous que j’ai pu être formée à la recherche. A Monsieur le Docteur Jean-Luc Daval, co-directeur du laboratoire et directeur de thèse, de m’avoir accepté comme doctorante sur ce projet, de m’avoir accordé votre confiance et votre soutien. De nous avoir permis à tous d’atteindre nos objectifs au cours de ces années. Merci pour votre sérénité qui m’a aidé à concrétiser ce manuscrit dans les meilleures conditions ! Merci de m’avoir soutenu et permis de développer ma passion pour la recherche. A Madame le Docteur Carine Bossenmeyer-Pourié, co-directrice de thèse, de m’avoir accepté en premier lieu pour un stage d’initiation de Licence 3 puis de Master 1 et de Master 2, pour finalement aboutir à cette thèse. Vous m’avez soutenu en 1ère ligne, permis de m’affirmer et de confirmer mes objectifs professionnels. C’est vous qui m’avez permis de tomber dans cette potion magique qui vous transforme, sur un plan professionnel et personnel. A Mademoiselle Racha Kerek, Docteur de l’université de Lorraine, première amie au sein du laboratoire et coéquipière en 1ère ligne au cours de ma première année de thèse. A toi qui m’a formé à la paillasse, avec qui on a tant rit et parfois tant désespéré quand les manips se décidaient à ne plus fonctionner ! A Mademoiselle Déborah Helle, technicienne, pour avoir contribué à ces travaux, pour m’avoir formé dans ses domaines de spécialité et pour avoir eu la patience de répondre à toutes mes questions. Merci aussi d’avoir le sang chaud, comme moi, ce qui nous a permis parfois, dans une bonne dispute de faire retomber la pression pour repartir de plus belle ! A Monsieur le Docteur Grégory Pourié, pour avoir pris le temps de m’enseigner et de m’épauler pour toutes les manips de comportement et surtout … pour les statistiques ! A Madame Maryvonne Merlet ainsi que Monsieur Arnaud Billon d’avoir supporté mes plaintes, mes angoisses, mes récits ; sur l’avancement de ma thèse, de ma rédaction et encore de ma rédaction ! Ca y est c’est fini ! Merci pour la relecture, une petite couche en plus au cas où vous n’en ayez pas assez entendu parler ! A Madame le Docteur Natacha Dreumont, merci ! D’avoir été là pour m’écouter, me rassurer et me conseiller pour la suite. Prochaines étapes : post-doc, publis et qualifs ! Pleins d’autres questions en perspectives … A Mademoiselle Justine Flayac, technicienne, pour transmettre tous les jours sa bonne humeur au laboratoire (oui oui, tu sais, tes farces ? … auxquelles j’ai réussi à échapper !). Merci tout particulier de m’avoir permis d’acquérir deux petits monstres félidés qui m’ont souvent obligé à souffler … en m’empêchant de travailler ! A Mademoiselle Aurélie Robert, technicienne, merci pour la seconde couche de bonne humeur ! Je t’avais promis de commémorer ta magnifique danse des canards du couloir pour nous rassembler au déjeuner. Voici chose faite et juste revanche pour m’avoir fait endosser un costume de lutin pour le Noël de l’unité ! A Mesdames Catherine Tavera et Dominique Guillaume, secrétaires, toujours les dernières au courant des potins ? Je ne dirais pas ça … Merci pour ces midis en votre compagnie, ces rires et sympathiques souvenirs en compagnie de Mademoiselle Justine Paoli. Merci à tous les doctorants de l’unité : Eva Feirgova, Rose Ghemrawi, Hassan Mehem, Anaïs Bison, Nicolas Martin, Sarah El Chakkour, Jérémy Willekens et tous les autres … pour tous ces bons moments … Merci à tous les membres de l’unité : Rémy Umoret, Sophie Lorentz, Aurélie Robert, Jean-Marc Alberto, Céline Chery, Pierre Rouyer, Fereshteh Amogli, Sebastien Hergalant, Philippe Gérard, Elise Jeannesson, Catherine Masson … pour la transmission de vos compétences… De même que Florence Coste. Merci à tous les Professeurs et Docteurs de l’unité : Rosa-Maria Rodriguez-Guéant, Shu-Fang Battaglia, Brigitte Leninger, Bernard Namour, Franck Hansmannel, Carole Arnold, David Coelho, Rémi Houlgatte … pour la transmission de votre savoir … Remerciements particuliers, pour toute l’équipe pédagogique avec qui j’ai effectué mon monitorat, Mesdames et Monsieur les Professeurs et Docteurs Dominique Chardard, Sandra Kuntz, Sabine Mazerbourg, Noémie Thomas, Marielle Thomas et Nadège Touche. Vous m’avez permis de sortir la tête de mon travail de thèse, pour participer aux enseignements que j’apprécie tout autant. Merci à mes parents, Albine et Claude Geoffroy, pour m’avoir inspiré, motivé et accompagné. Pour me soutenir dans mes projets … TABLE DES MATIERES LISTE DES FIGURES …………………………………………………………………... VII LISTE DES SCHEMAS DE SYNTHESE ……………………………………………….. IX LISTE DES TABLEAUX ………………………………………………………………..… X LISTE DES FICHES TECHNIQUES …………………………………………..……….. XI LISTE DES ABREVIATIONS …………………………………………………………. XIII ___________________________________________________________________________ AVANT PROPOS ………………………………………………...………………………… 1 - De l’observation à la compréhension : pathologies et nutrition ……………………. 1 - L’émergence de l’embryologie et de la tératologie ………………………………… 2 - Rôle des instances en charge de la santé publique ………………………………….. 3 - Les limites liées au contexte socio-économique ……………………………………. 3 - Etat de la recherche et problématiques ……………………………………………... 4 SYNTHESE BIBLIOGRAPHIQUE ………………………………………………………. 5 I. Développement du système nerveux ……………………………………………….. 7 1. Embryogenèse et croissance fœtale ……………………………………………… 7 2. Neurulation et mise en place anatomique du système nerveux …………………... 8 3. Expansion du système nerveux ………………………………………………..... 13 4. Période fœtale : croissance cérébrale et mises en place fonctionnelle ………...... 15 5. Architecture cérébrale et fonctionnalités ……………………………………….. 20 II. Déterminants du neuro-développement ………………………………………….. 25 1. Voies de régulation épigénomique et épigénétique de l’expression des gènes …. 28 a. Modification de l’ADN et des histones …………………………………. 28 b. Modification des histones ……………………………………………….. 33 2. Régulation post-transcriptionnelle de l’expression des protéines par les miRs … 36 a. Biogenèse des ARN non-codants de type miRs ………………………… 36 b. Mode d’action du complexe miRISC …………………………………… 39 L c. Interventions des miRs dans le système nerveux central ……………….. 39 3. Régulation des voies de signalisation par les miRs ……………………………... 43 a. Prolifération, différenciation et survie ……………………………...….. 43 b. Maturation, plasticité synaptique et mémorisation ……………………… 55 c. Altération de l’expression des miRs et anomalies du SNC ……………... 60 4. Voies de régulation mises en jeu ………………………………………………... 63 a. STAT3 …………………………………………………………………... 63 b. Dll1/Notch ………………………………………………………………. 66 c. Récepteurs AMPA/NMDA …………………………………………...… 67 III. Vitamines
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