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# Annexes à l'article en préparation

## Annexe – Vidéos de locomotion des souris

1) Vidéo de la locomotion d'une souris CTL âgée de 2 mois – CatWalk

2) Vidéo de la locomotion d'une souris Mbnl1-KO âgée de 2 mois – CatWalk

3) Vidéo de la locomotion d'une souris dKO âgée de 2 mois – CatWalk

4) Vidéo de la locomotion d'une souris CTL âgée de 4 mois – Catwalk

5) Vidéo de la locomotion d'une souris Mbnl1-KO âgée de 4 mois – CatWalk

6) Vidéo de la locomotion d'une souris dKO âgée de 4 mois – CatWalk

## Annexe – Tables supplémentaires

1) Tables supplémentaires S1 à S4 – Analyse de l'épissage alternatif associée au séquençage ARN

2) Tables supplémentaires S5 à S7 – Analyse EnrichR
Table des figures

<table><tr><td>Figure 1 : Représentation schématique du gène DMPK</td><td>8</td></tr><tr><td>Figure 2 : Catégories de patients DM1 et principaux symptômes associés</td><td>9</td></tr><tr><td>Figure 3 : Phénomène d'anticipation entre les générations mis en évidence par une famille atteinte de DM1</td><td>10</td></tr><tr><td>Figure 4 : Représentation schématique du gène CNBP</td><td>11</td></tr><tr><td>Figure 5 : Principaux symptômes associés à la DM2</td><td>12</td></tr><tr><td>Figure 6 : Symptômes plurisystémiques de la DM</td><td>13</td></tr><tr><td>Figure 7 : La myotonie chez les patients DM</td><td>14</td></tr><tr><td>Figure 8 : Défauts histologiques du muscle squelettique chez les patients DM1 et DM2</td><td>16</td></tr><tr><td>Figure 9 : Foci ARN dans la DM1 et la DM2</td><td>22</td></tr><tr><td>Figure 10 : MBNL est séquestré par les foci ARN dans le noyau des cellules DM</td><td>25</td></tr><tr><td>Figure 11 : Mécanisme pathologiques principaux de la DM</td><td>27</td></tr><tr><td>Figure 12 : Gènes MBNL1, MBNL2 et MBNL3 et transcrits associés chez les vertébrés</td><td>43</td></tr><tr><td>Figure 13 : Niveaux relatifs d'expression des ARNm des gènes MBNL1, MBNL2 et MBNL3 dans différents tissus</td><td>44</td></tr><tr><td>Figure 14 : Représentation schématique du mécanisme d'épissage alternatif</td><td>52</td></tr><tr><td>Figure 15 : Représentation schématique de l'effet de la liaison de MBNL sur l'épissage alternatif de ses cibles</td><td>53</td></tr><tr><td>Figure 16 : Représentation schématique de l'effet de la liaison de MBNL sur le choix du site de polyadénylation de ses cibles</td><td>55</td></tr><tr><td>Figure 17 : Représentation schématique du rôle de MBNL sur la localisation des ARNm</td><td>57</td></tr><tr><td>Figure 18 : Représentation schématique du faisceau corticospinal</td><td>60</td></tr><tr><td>Figure 19 : Connexions synaptiques d'un MN somatique</td><td>62</td></tr><tr><td>Figure 20 : Génération des domaines progéniteurs du tube neural</td><td>63</td></tr><tr><td>Figure 21 : Segmentation en colonnes des domaines motoneuronaux de la moelle épinière</td><td>65</td></tr><tr><td>Figure 22 : Représentation schématique de la transmission synaptique entre un MN supérieur et un MN spinal</td><td>68</td></tr><tr><td>Figure 23 : Représentation schématique de la génération du potentiel de plaque à la JNM</td><td>72</td></tr><tr><td>Figure 24 : Marquages de la JNM de la souris</td><td>75</td></tr><tr><td>Figure 25 : Représentation schématique du déclenchement de la voie de signalisation Agrine-Lrp4-MuSK</td><td>77</td></tr></table>
<table><tr><td>Figure 26 : Evolution morphologique de la JNM au cours du développement</td><td>80</td></tr><tr><td>Figure 27 : Représentation schématique du couplage excitation-contraction</td><td>84</td></tr><tr><td>Figure 28 : JNM des souris Hb9Cre-Mbnl2-KO de 1 an</td><td>123</td></tr><tr><td>Figure 29 : L'injection d'AAV-shMBNL provoque la diminution importante de Mbnl1 et Mbnl2 spécifiquement dans le muscle squelettique</td><td>126</td></tr><tr><td>Figure 30 : La depletion simultanée de Mbnl1 et Mbnl2 dans le muscle squelettique adulte induit des défauts structuraux progressifs de la JNM</td><td>128</td></tr><tr><td>Figure 31 : La perte de MBNL dans le muscle squelettique n'induit pas de défauts manifestes de la communication neuromusculaire</td><td>130</td></tr><tr><td>Figure 32 : Les JNM des souris HSA<sup>LR</sup> reproduisent certains défauts postsynaptiques des souris déplétées de MBNL dans le muscle squelettique</td><td>132</td></tr><tr><td>Figure 33 : La perte de Mbnl1 et Mbnl2 spécifiquement dans les MNs induit l'inclusion de l'exon 35 de l'agrine</td><td>143</td></tr><tr><td>Figure 34 : La perte de MBNL dans l'unité motrice n'altère pas l'homéostasie de l'AChE</td><td>149</td></tr></table>
Table des tableaux

<table><tr><td>Tableau 1 : Événements d'épissage alternatif altérés et associés aux symptômes de la DM.</td><td>29</td></tr><tr><td>Tableau 2 : Modèles murins avec répétitions CTG.</td><td>38</td></tr><tr><td>Tableau 3 : Modèles murins d'expression de MBNL et CELF1.</td><td>39</td></tr><tr><td>Tableau 4 : Stratégies thérapeutiques pour la DM1.</td><td>41</td></tr></table>
## Abréviations

* α-BTX : α-bungarotoxine

* AAV : Adénovirus adéno-associé

* ACh : Acétylcholine

* AChE : Acétylcholine estérase

* ALE : Exons terminaux alternatifs

* AMP : Adénosine monophosphate

* AMPA : Acide propionique α-amino-3-hydroxy-5-methyl-4-isoxazole

* AMPK : Kinase activée par l'AMP

* APA : *Alternative cleavage and polyadenylation*

* APP : Protéines précurseurs de l'amyloïde

* ASO : Oligonucléotides antisens

* ATP : Adénosine triphosphate

* BIN1 : Protéine 1 d'interaction dépendante de la boîte myc

* BMP : *bone morphogenetic protein family*

* CACNA1C : Sous-unité alpha 1C du canal calcique voltage-dépendant

* CACNA1D : Sous-unité alpha 1D du canal calcique voltage-dépendant

* CACNA1S : Sous-unité alpha 1S du canal calcique voltage-dépendant

* CaMKII : Kinase II dépendant de Ca²⁺/calmoduline

* CAPN2 : Calpain-2

* CDK : kinase cycline-dépendante

* CELF : CUGBP Elav-like family member

* ChAT : Choline acétyltransferase

* CHRNE : Sous-unité epsilon du RACH

* CHRNG : Sous-unité gamma du RACH

* CLASP : Cytoplasmic Linker Associated Protein

* CLC-1/CLCN1 : Canal chlorure 1 voltage-dépendant

* CLIP-Seq : Cross-linking and immunoprecipitation sequencing

* CMAP : *Compound muscle action potential*

* CNBP : CCHC-type zinc finger nucleic acid binding

* CNS : Système nerveux central

* ColQ : Collagène Q

* CRISPR : Clustered, regularly interspersed palindromic repeats

* CSEs : Cellules souches embryonnaires

* CTL : Contrôle

* DDX : DEAD box protein

* DGC : Complexe glycoprotéique associé à la dystrophine

* DHPR : Récepteur à la dihydropyridine

* dKO : Double KO

* DM : Dystrophie myotonique

* DM1 : Dystrophie myotonique de type 1

* DM2 : Dystrophie myotonique de type 2

* DMD : Dystrophine ou dystrophie musculaire de Duchenne

* DMPK : Dystrophia myotinica protein kinase

* DMWD : DM1 locus, WD repeat containing

* Dok7 : *Docking Protein 7*

* Dvl1 : *Dishevelled Segment Polarity Protein 1*

* ECG : Électrocardiogramme

* EGFP : Enhanced green fluorescent protein
eIF2 : Facteur eukaryote d'initiation 2

EMG : Électromyogramme

Ex. : Exon

Ex. alt : Exon alternatif

FDR : *False discovery rate*

FISH : Hybridation fluorescente *in situ*

FOXP1 : Forkhead box protein 1

GDNF : Facteur extrinsèque neurotrophique des cellules gliales

GJA1 : Protéine alpha-1 des jonctions communicantes

GLI : *GLI-Kruppel family*

GRIN 1 : Glutamat Receptor Ionotropic N-Methyl D-Aspartate de type 1

GRP1 : Glutamate Receptor Interacting Protein 1

GSK3β : Glycogène kinase synthase 3 beta

Hb9 : Homeobox 9

hcTnT : Troponine cardiaque humaine

HDAC : Histone deacetylase

HMC : Colonne hypaxiale motrice

hnRNP : heterogeneous nuclear ribonucleoproteine

HOX : Famille homeobox

HSA<sup>LR</sup> : Actine squelettique humaine *longues répétitions*

INSR : Récepteur à l'insuline

JNM : Jonction neuromusculaire

KA : Kainate

KIF : Kinesin-like protein

KO : Knockout

LDB3 : Protéine à domaine de liaison LIM 3

LIF : Facteur inhibiteur de la leucémie

LMC : Colonne latérale motrice

Lrp4 : *low-density lipoprotein receptor-related protein 4*

MAPT : Protéine Tau associée aux microtubules

Mbl : Muscleblind

MBNL : Muscleblind-like

MEF2 : Myocyte enhancer factor-2

MET/TEM : Microscopie électronique à transmission

MMC : Colonne médiane motrice

MN : Motoneurone

MT : Microtubule

mTORC1 : *Mechanistic Target Of Rapamycin Kinase complex 1*

MuSK : Kinase muscle-spécifique

MYH6 : Chaîne lourde de la myosine

Myo : Myogénine

MyoD : Myoblast determination protein 1

NEUROG2 : Neurogénine 2

NF : Neurofilament

NKK2-5 : NK2 homebox 5

NMD : nonsense-mediated mRNA decay
NMDA : Acide N-méthyl-D-aspartique

NMDAR : Récepteur au NMDA

Nrg1 : Neuréguline 1

OLIG1&2 : Protéines 1 et 2 facteurs de transcription des oligodendrocytes

OPCs : Progéniteurs d'oligodendrocytes

pA : Polyadénylation

PCP : *Planar cell polarity*

PGC : Colonne préganglionique motrice

PH : Domaine d'homologie aux pleckstrines

PI : Post-injection

PITCH1 : *patched homolog 1 receptor*

PKC : Protéine kinase C

PKM2 : Pyruvate kinase musculaire 2

PMC : Colonne phrénique motrice

PMO : Morpholino oligonucleotides phosphorodiamidate

PROMM : Dystrophie myotonique proximale

PTB : Domaine de liaison aux phosphotyrosines

PTIX2 : Paired like homeodomain 2

RA : Acide rétinoïque

RACh/AChR : Récepteur à l'acétylcholine

RARγ : Récepteur gamma à l'acide rétinoïque

RBFOX : RNA binding Fox-1 homolog

RBP : Protéine de liaison à l'ARN

RGS4 : *regulator of G protein signaling 4*

RNP : Ribonucléoprotéine

RS : Réticulum sarcoplasmique

RYR1 : Récepteur à la ryanodine

SAC : Colonne spinale accessoire

SC : Moelle épinière

SCIA : Nerf sciatique

SCN5A : Sous-unité alpha du canal sodique voltage dépendant V

SERCA/ATP2A1 : Pompe ATPase calcique du réticulum sarcoplasmique

SHARP : Protéine de répression associée à SMRT/HDAC1

SHH : *Sonic hedgehog morphogen*

shmiR : Petit miARN en épingle à cheveux

SIX5 : SIX homeobox 5

SLA : Sclérose latérale amyotrophique

SMO : *smoothened homolog*

SMRT : Silencing mediator for retinoid and thyroid receptors

SNARE : *Soluble N-ethylmaleimide-sensitive factor Attachment protein Receptor*

SNP : Système nerveux périphérique

SORBS : *Sorbin And SH3 Domain Containing*

SP1 : Specificity protein 1

Spag9 : kinase c-jun-amino-terminale

STAUFEN1 : Staufen homolog 1

SUPT4H1 : SPT4 Homolog, DSIF Elongation Factor Subunit

Syn : Synaptophysine

TA : Tibialis antérieur

TALEN : Transcription activator-like effector nucleases

TANC2 : Tetratricopeptide Repeat, Ankyrin Repeat And Coiled-Coil Containing 2

tSC : Cellule de Schwann terminale
Tubules T : Tubules transverses

Wls : Médiateur de sécrétion du ligand Wnt

Wnt : wingless-type MMTV integration site family

ZnF : Doigt-de-zinc

ZNF9 : CNBP
Résumé :

La dystrophie myotonique de type 1 (DM1) est une maladie rare héréditaire avec des atteintes musculaires, cardiaques et cognitives. La DM1 est due à des expansions de répétitions CTG dans la partie 3'UTR du gène *DMPK*. Les ARN DMPK mutés s'agrègent et séquestrent les protéines de liaison à l'ARN Muscleblind-like (MBNL), menant à des anomalies du métabolisme des ARNs dans plusieurs tissus. La famille MBNL est composée de MBNL1, 2 et 3 mais seuls MBNL1 et 2 sont exprimés dans le système nerveux. Alors que le muscle est largement étudié dans la DM1, des études antérieures suggèrent également une altération de la communication entre les motoneurones (MNs) et le muscle squelettique via la jonction neuromusculaire (JNM). Pour déterminer le rôle des protéines MBNL dans les MNs, nous avons généré des souris MN-dKO invalidées pour Mbnl2 spécifiquement dans les MNs (MN-Mbnl2-KO) avec une déplétion constitutive de Mbnl1 (Mbnl1-KO). Les souris MN-Mbnl2-KO ne présentent pas de phénotype, cependant les souris MN-dKO développent progressivement des défauts de coordination par rapport aux souris Mbnl1-KO. Chez les souris âgées de 4 mois, les troubles moteurs des souris MN-dKO s'accompagnent d'anomalies structurales et ultrastructurales sévères et globales de la JNM. A contrario, les altérations de la JNM des souris Mbnl1-KO semblent cantonnées à la partie post-synaptique. Ainsi, la perte de Mbnl1 et Mbnl2 dans les MNs aggrave les altérations de la JNM causées par la perte de Mbnl1 seul. Une analyse plus précoce chez des souris âgées de 2 mois a permis de montrer que les JNM des souris MN-dKO présentent des défauts structuraux par rapport aux JNM des souris contrôles mais aussi Mbnl1-KO. En revanche, et malgré leur aspect anormal, les JNM des souris MN-dKO de 2 mois sont matures. Ces résultats suggèrent que les protéines MBNL1 et MBNL2 jouent un rôle dans le maintien des JNM et que les conséquences de la perte de Mbnl1 et Mbnl2 dans les MNs sont plus sévères, globales et se manifestent plus précocement que celles de la perte de Mbnl1 seul.

Afin d'identifier les cibles dérégulées par la perte de Mbnl1 et/ou Mbnl2 dans les MNs, un séquençage ARN à haut-débit, associé à une analyse bio-informatique de l'épissage alternatif, a été réalisé à partir d'ARN extrait de moelles épinières lombaires des souris MN-dKO, MN-Mbnl2-KO, Mbnl1-KO et contrôles âgées de 4 mois. Cette analyse a mis en évidence de nombreuses cibles spécifiques aux souris MN-dKO, et donc à la perte conjointe de Mbnl1 et Mbnl2. De manière intéressante, l'analyse GO-Term des ARN cibles communs aux souris MN-dKO et MN-Mbnl2-KO ou Mbnl1-KO a permis de montrer que la perte de MBNL2 affecte la maturation de gènes impliqués dans le transport de neurotransmetteurs ou l'amarrage des vésicules synaptiques alors que la perte de MBNL1 affecte la maturation de gènes impliqués dans les processus d'endocytose. Ainsi, MBNL1 et MBNL2 seraient impliqués dans des processus différents au sein des MN.

Afin de compléter l'étude du rôle des protéines MBNL dans la maintenance de la JNM et de la communication neuromusculaire, des souris WT adultes ont été injectées avec des *adeno-associated adenovirus*
exprimant un shmiR ciblant Mbnl1 et Mbnl2 spécifiquement dans le muscle squelettique. 2 mois post-injection (PI), les JNMs de ces souris récapitulent en partie les anomalies observées chez les souris Mbnl1-KO âgées de 4 mois, confirmant un rôle de Mbnl1 dans le muscle squelettique sur le maintien de la JNM. Ces anomalies post-synaptiques s'étendent progressivement au côté présynaptique de la jonction 4 mois PI. Cette aggravation confirme le rôle de MBNL1 dans le muscle squelettique sur le maintien de la JNM.

L'ensemble de mes travaux de thèse soulignent l'importance des protéines MBNL dans les MNs pour la communication neuromusculaire et suggèrent, pour la première fois, que la perte de MBNL dans les MNs pourrait contribuer à la physiopathologie musculaire de la DM1.

Mots clés : MBNL – Motoneurone – Dystrophie myotonique – Jonction neuromusculaire – Modèle de souris – ARN
# MBNL loss in motoneurons: impact on motor unit function in Myotonic Dystrophy

## Abstract:

Myotonic dystrophy type 1 (DM1) is a rare inherited disease with muscle, heart and cognitive impairments. DM1 is caused by CTG repeat expansions in the 3'UTR of the DMPK gene. DMPK mutated RNAs aggregate and sequester Muscleblind-like RNA (MBNL) binding proteins, leading to RNA metabolism abnormalities in several tissues. The MBNL family is composed of MBNL1, 2 and 3 but only MBNL1 and 2 are expressed in the nervous system. While skeletal muscle has been extensively studied in DM1, previous reports also suggest an impairment of communication between motor neurons (MNs) and skeletal muscle through the neuromuscular junction (NMJ) in DM1. To determine the role of MBNL proteins in MNs, we generated MN-dKO mice invalidated for Mbnl2 specifically in MNs (MN-Mbnl2-KO) in a Mbnl1 null background (Mbnl1-KO). MN-Mbnl2-KO mice don't manifest a phenotype, however MN-dKO mice progressively develop coordination defects compared to Mbnl1-KO mice. In 4-month-old mice, MN-dKO mice motor disorders are accompanied by severe and global structural and ultrastructural abnormalities of the NMJ. In contrast, Mbnl1-KO mice NMJ alterations seem to be confined to the post-synaptic part. Thus, the loss of Mbnl1 and Mbnl2 in MNs exacerbates NMJ alterations caused by the loss of Mbnl1 alone. Interestingly, NMJs from younger MN-dKO mice exhibit early structural defects compared to NMJs from control and Mbnl1-KO mice, which are unaffected. However, and despite their abnormal appearance, NMJs of MN-dKO mice are mature at this age. These results suggest that MBNL1 and MBNL2 proteins play a role in the NMJ maintenance. Furthermore, defects caused by the Mbnl1 and Mbnl2 loss in MNs are more severe, global but also manifest earlier than those caused by the loss of Mbnl1 alone.

In order to identify RNA targets deregulated by the loss of Mbnl1 and/or Mbnl2 in MNs, we conducted high-throughput RNA sequencing, using RNA extracts from lumbar spinal cords of 4 months old MN-dKO; MN-Mbnl2-KO; Mbnl1-KO and control mice. An alternative splicing analysis revealed numerous targets specific to MN-dKO mice, thus due to the simultaneous loss of Mbnl1 and Mbnl2. Interestingly, GO-Term analysis of RNA targets common to MN-dKO and MN-Mbnl2-KO or Mbnl1-KO mice showed that MBNL2 loss in MNs affects the maturation of genes involved in neurotransmitter transport or synaptic vesicle docking whereas MBNL1 loss affects the maturation of genes involved in endocytosis processes. Thus, MBNL1 and MBNL2 may be involved in different processes in MNs.

To complete the study of the role of MBNL proteins in NMJ and neuromuscular communication maintenance, adult WT mice were injected with adeno-associated adenovirus expressing a shmiR targeting Mbnl1 and Mbnl2 specifically in skeletal muscle. 2 months post-injection (PI), NMJs from these mice partly recapitulated NMJ defects observed in 4-month-old Mbnl1-KO mice, confirming a role for Mbnl1 in skeletal muscle on JNM maintenance. These postsynaptic abnormalities progressively extend to the
presynaptic side of the junction 4 months PI. This aggravation confirms the role of MBNL1 in skeletal
muscle on NMJ maintenance.

The whole of my thesis work highlights the importance of MBNL proteins in MNs for neuromuscular communication. My work suggests, for the first time, that MBNL loss in MNs may contribute to DM1 muscle pathophysiology.

Keywords: MBNL – Motoneuron – Myotonic dystrophy – Neuromuscular junction – Mouse model – RNA