Tau exon 2 responsive elements deregulated in myotonic dystrophy type I are proximal to exon 2 and synergistically regulated by MBNL1 and MBNL2.
The splicing of the microtubule-associated protein Tau is regulated during development and is found to be deregulated in a growing number of pathological conditions such as myotonic dystrophy type I (DM1), in which a reduced number of isoforms is expressed in the adult brain. DM1 is caused by a dynamic and unstable CTG repeat expansion in the DMPK gene, resulting in an RNA bearing long CUG repeats (n>50) that accumulates in nuclear foci and sequesters CUG-binding splicing factors of the muscle blind-like (MBNL) family, involved in the splicing of Tau pre-mRNA among others. However, the precise mechanism leading to Tau mis-splicing and the role of MBNL splicing factors in this process are poorly understood. We therefore used new Tau minigenes that we developed for this purpose to determine how MBNL1 and MBNL2 interact to regulate Tau exon 2 splicing. We demonstrate that an intronic region 250 nucleotides downstream of Tau exon 2 contains cis-regulatory splicing enhancers that are sensitive to MBNL and that bind directly to MBNL1. Both MBNL1 and MBNL2 act as enhancers of Tau exon 2 inclusion. Intriguingly, the interaction of MBNL1 and MBNL2 is required to fully reverse the mis-splicing of Tau exon 2 induced by the trans-dominant effect of long CUG repeats, similar to the DM1 condition. In conclusion, both MBNL1 and MBNL2 are involved in the regulation of Tau exon 2 splicing and the mis-splicing of Tau in DM1 is due to the combined inactivation of both.
Inserm UMR837-1 and Univ. Lille Nord de France, Jean-Pierre Aubert Research Center, Alzheimer & Tauopathies, F-59045 Lille, France; Regional University Hospital of Lille, France.
C
C
Carpentier
Inserm UMR837-1 and Univ. Lille Nord de France, Jean-Pierre Aubert Research Center, Alzheimer & Tauopathies, F-59045 Lille, France; Regional University Hospital of Lille, France.
D
D
Ghanem
Inserm UMR837-1 and Univ. Lille Nord de France, Jean-Pierre Aubert Research Center, Alzheimer & Tauopathies, F-59045 Lille, France; Regional University Hospital of Lille, France.
F J
FJ
Fernandez-Gomez
Inserm UMR837-1 and Univ. Lille Nord de France, Jean-Pierre Aubert Research Center, Alzheimer & Tauopathies, F-59045 Lille, France; Regional University Hospital of Lille, France.
F
F
Jumeau
Laboratory of Molecular Engineering and Articular Pathophysiology (IMoPA), Nancy University - CNRS, UMR 7214, 7365 Vandoeuvre-les-Nancy, France.
J V
JV
Philippe
Department de Neurobiology & Genetics, IGBMC, Inserm U964, CNRS UMR7104, University of Strasbourg, Illkirch, France.
F
F
Freyermuth
Inserm UMR837-1 and Univ. Lille Nord de France, Jean-Pierre Aubert Research Center, Alzheimer & Tauopathies, F-59045 Lille, France; Regional University Hospital of Lille, France.
A
A
Labudeck
Inserm UMR837-1 and Univ. Lille Nord de France, Jean-Pierre Aubert Research Center, Alzheimer & Tauopathies, F-59045 Lille, France; Regional University Hospital of Lille, France.
S
S
Eddarkaoui
Inserm UMR837-1 and Univ. Lille Nord de France, Jean-Pierre Aubert Research Center, Alzheimer & Tauopathies, F-59045 Lille, France; Regional University Hospital of Lille, France.
C M
CM
Dhaenens
Wolfson Centre for Inherited Neuromuscular Disease, RJAH Orthopaedic Hospital, Oswestry, Shropshire, UK; Institute for Science and Technology in Medicine, Keele University, Keele, Staffordshire, UK.
I
I
Holt
Laboratory of Molecular Engineering and Articular Pathophysiology (IMoPA), Nancy University - CNRS, UMR 7214, 7365 Vandoeuvre-les-Nancy, France.
I
I
Behm-Ansmant
Laboratory of Molecular Engineering and Articular Pathophysiology (IMoPA), Nancy University - CNRS, UMR 7214, 7365 Vandoeuvre-les-Nancy, France.
N
N
Marmier-Gourrier
Laboratory of Molecular Engineering and Articular Pathophysiology (IMoPA), Nancy University - CNRS, UMR 7214, 7365 Vandoeuvre-les-Nancy, France.
C
C
Branlant
Department de Neurobiology & Genetics, IGBMC, Inserm U964, CNRS UMR7104, University of Strasbourg, Illkirch, France.
N
N
Charlet-Berguerand
Therapy of muscular diseases - Myology Institute, UPMC Univ. Paris 6, UM76/Inserm, U974/CNRS, UMR 7215, G.H. Pitié-Salpétrière - Bâtiment Babinski, Paris, France.
J
J
Marie
Inserm UMR837-1 and Univ. Lille Nord de France, Jean-Pierre Aubert Research Center, Alzheimer & Tauopathies, F-59045 Lille, France; Regional University Hospital of Lille, France.
S
S
Schraen-Maschke
Inserm UMR837-1 and Univ. Lille Nord de France, Jean-Pierre Aubert Research Center, Alzheimer & Tauopathies, F-59045 Lille, France; Regional University Hospital of Lille, France.
L
L
Buée
Inserm UMR837-1 and Univ. Lille Nord de France, Jean-Pierre Aubert Research Center, Alzheimer & Tauopathies, F-59045 Lille, France; Regional University Hospital of Lille, France. Electronic address: nicolas.sergeant@inserm.fr.
N
N
Sergeant
Inserm UMR837-1 and Univ. Lille Nord de France, Jean-Pierre Aubert Research Center, Alzheimer & Tauopathies, F-59045 Lille, France; Regional University Hospital of Lille, France. Electronic address: marie-laure.caillet@inserm.fr.
M L
ML
Caillet-Boudin
D001483:Base Sequence; D045744:Cell Line, Tumor; D005091:Exons; D006801:Humans; D008969:Molecular Sequence Data; D009223:Myotonic Dystrophy / Q000235:genetics*; D012326:RNA Splicing; D016601:RNA-Binding Proteins / Q000502:physiology*; D020218:Response Elements; D016875:tau Proteins / Q000235:genetics*
C493663:MBNL1 protein, human; C499444:MBNL2 protein, human; D016601:RNA-Binding Proteins; D016875:tau Proteins
Microtubule-associated protein Tau; Muscleblind-like protein; Myotonic dystrophy; Splicing; Tauopathies