Laffaire, Julien (2008) Modifications du transcriptome au cours du développement postnatal du cervelet dans un modèle murin de Trisomie 21. PhD thesis Neurosciences, Laboratoire de Neurobiologie et Diversité Cellulaire, ESPCI p.189.

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Abstract

La Trisomie 21, ou syndrome de Down, est causée par la présence d’une troisième

copie du chromosome 21. De récentes analyses ont démontré une surexpression des gènes

en 3 copies avec des effets de compensation ou d’amplification pour certains d’entre eux.

Cependant, l’impact de l’effet de dosage génique sur l’ensemble du transcriptome est

encore débattu.

C’est pourquoi nous avons mené une analyse de l’expression des gènes chez la souris

Ts1Cje, un modèle murin de la Trisomie 21, au cours du développement postnatal du cervelet.

En effet, nous avons montré dans ce modèle une diminution de la prolifération dans

le cervelet à la naissance ainsi qu’une diminution du volume du cervelet chez l’adulte.

L’analyse statistique de données de puces à ADN a révélé un effet majeur de dosage génique

des gènes en 3 copie ainsi que de gènes présents sur un fragment délété de 2 Mb

que nous avons pour la première caractérisé par hybridation génomique comparative. Cet

effet de dosage génique n’influe que modérément sur le transcriptome : 2,4 à 7,5% des

gènes exprimés sont régulés. De plus, nous n’avons trouvé que 13 gènes significativement

régulés tout au long du développement postnatal du cervelet dont 6 correspondants à des

gènes en 3 copies. Enfin, l’analyse de transcriptome à partir de dissections de la couche

granulaire externe de cervelet, où nous avons démontré une réduction de la prolifération

à la naissance, a révélé un effet majeur de dosage génique mais pas de déstabilisation

globale du transcriptome.

Toutes ces données suggèrent qu’un nombre restreint de gènes présents en 3 copies

sont responsables du phénotype présent dans le cervelet des souris Ts1Cje. Nous proposons

une liste courte de gènes candidats.

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Table of content

Remerciements v

Table des matières ix

Liste des figures xi

Liste des tableaux xiii

Résumé xv

Abstract xvi

Introduction -1

1 De la Trisomie21 -2

1.1 De l’idiotie à la Trisomie21 - 3

1.2 Caractéristiques cliniques de la Trisomie21 - 5

1.2.1 Caractéristiques craniofaciales et anomalies du squelette - 5

1.2.2 Cerveau, Cognition et Comportement - 6

1.2.3 Malformations viscérales - 8

1.2.4 Défaillance du système immunitaire - 9

1.2.5 Troubles hormonaux - 10

1.3 Épidémiologie, Étiologie et Mécanisme - 12

2 Du chromosome 21 -14

2.1 Cartographie du Chromosome21 - 14

2.2 Contenu génique duChromosome21 - 15

2.3 Le protéome du Chromosome21 - 16

2.4 Comparaisond e la séquence du chromosome21 - 18

3 Des modèles d’étude de la Trisomie 21 -20

3.1 Les modèles de trisomie partielle - 21

3.1.1 Ts16 - 21

3.1.2 Ts65Dn - 21

3.1.3 Ts1Cje - 23

3.1.4 Ms1/Ts65Dn - 24

3.1.5 Ts1Rhr etMs1Rhr/Ts65Dn - 25

ix

3.1.6 Ts1YahetTs2Yah - 25

3.2 Les modèles trans-chromosomiques - 26

3.2.1 Tc1 - 26

3.3 Les modèles murins monogéniques - 28

3.4 Limitations des modèles murins - 30

4 Des modifications de l’expression des gènes dans la Trisomie 21 31

4.1 Les puces à ADN - 31

4.2 L’effet du dosage génique - 34

4.3 Quelles conséquences sur le transcriptome? - 38

4.4 ‘Effet de dosage génique’ ou ‘rupturede l’homéostasie’? - 39

5 Hypothèses et objectifs de travail -41

5.1 Contexte - 41

5.2 Pathologie du cervelet dans laTrisomie21 - 42

5.3 Caractérisation du phénotype cérébelleux - 44

5.4 Analyse du transcritome au cours du développement du cervelet - 45

5.5 Caractérisation du génome de la lignéeTs1Cje - 45

Matériels et Méthodes -47

Les souris Ts1Cje -48

Marquages immunohistochimiques -49

Imagerie par résonance magnétique -53

Analyse du transcriptome avec des puces RNG/MRC- 55

Analyse du transcriptome avec des puces Illumina -58

Analyse du génome par puce CGH -60

Mesure de l’expression des gènes par PCR quantitative en temps réel -62

Résultats -66

1 Etude morphologique et histologique du cervelet -67

1.1 Réduction duvolumedu cervelet - 67

1.2 Réduction de la prolifération des cellules granulaires - 68

2 Étude du transcriptome au cours du développement du cervelet -73

2.1 Les modifications du transcriptome chez la sourisTs1Cje - 84

2.2 Les gènes impliqués dans développement du cervelet - 88

2.3 Les gènes impliqués dans la prolifération des cellules granulaires - 90

3 Étude du transcriptome de la couche externe à la naissance -93

x

4 Identification d’une monosomie partielle du chromosome 12 -107

Discussion 111

1 Validation de notre modèle d’étude -114

1.1 L’influence du fond génétique -114

1.2 L’hypoplasie cérébelleuse est-elle spécifique à la Trisomie 21? - 115

1.3 La délétion décelée invalid- t-elle le modèle Ts1Cje ? - 117

2 Quelle est l’origine de la diminution de la prolifération ? -121

2.1 Ce que nous apprennent les levures - 122

2.2 Une ou des modifications de la prolifération? - 123

2.3 Trisomie21 et cancer - 126

3 Les modifications du transcriptome -128

4 A la recherche des gènes candidats -134

4.1 Des stratégies mises en oeuvre - 134

4.2 Etablissement du gène candidat - 136

Conclusions et Perspectives -140

Annexes -143

Bibliographie -154

Publications -172

xi

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