title: Analysis of exonic regions involved in nuclear localization, splicing activity, and dimerization of Muscleblind-like-1 isoforms.
abstract: Muscleblind-like-1 (MBNL1) is a splicing regulatory factor controlling the fetal-to-adult alternative splicing transitions during vertebrate muscle development. Its capture by nuclear CUG expansions is one major cause for type 1 myotonic dystrophy (DM1). Alternative splicing produces MBNL1 isoforms that differ by the presence or absence of the exonic regions 3, 5, and 7. To understand better their respective roles and the consequences of the deregulation of their expression in DM1, here we studied the respective roles of MBNL1 alternative and constitutive exons. By combining genetics, molecular and cellular approaches, we found that (i) the exon 5 and 6 regions are both needed to control the nuclear localization of MBNL1; (ii) the exon 3 region strongly enhances the affinity of MBNL1 for its pre-mRNA target sites; (iii) the exon 3 and 6 regions are both required for the splicing regulatory activity, and this function is not enhanced by an exclusive nuclear localization of MBNL1; and finally (iv) the exon 7 region enhances MBNL1-MBNL1 dimerization properties. Consequently, the abnormally high inclusion of the exon 5 and 7 regions in DM1 is expected to enhance the potential of MBNL1 of being sequestered with nuclear CUG expansions, which provides new insight into DM1 pathophysiology.
authors: INSERM, U837, Alzheimer and Tauopathies, Lille, France.
authors: Hélène
authors: H
authors: Tran
authors: Nathalie
authors: N
authors: Gourrier
authors: Camille
authors: C
authors: Lemercier-Neuillet
authors: Claire-Marie
authors: CM
authors: Dhaenens
authors: Audrey
authors: A
authors: Vautrin
authors: Francisco José
authors: FJ
authors: Fernandez-Gomez
authors: Ludovic
authors: L
authors: Arandel
authors: Céline
authors: C
authors: Carpentier
authors: Hélène
authors: H
authors: Obriot
authors: Sabiha
authors: S
authors: Eddarkaoui
authors: Lucie
authors: L
authors: Delattre
authors: Edwige
authors: E
authors: Van Brussels
authors: Ian
authors: I
authors: Holt
authors: Glenn E
authors: GE
authors: Morris
authors: Bernard
authors: B
authors: Sablonnière
authors: Luc
authors: L
authors: Buée
authors: Nicolas
authors: N
authors: Charlet-Berguerand
authors: Susanna
authors: S
authors: Schraen-Maschke
authors: Denis
authors: D
authors: Furling
authors: Isabelle
authors: I
authors: Behm-Ansmant
authors: Christiane
authors: C
authors: Branlant
authors: Marie-Laure
authors: ML
authors: Caillet-Boudin
authors: Nicolas
authors: N
authors: Sergeant
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000235:genetics; D017398:Alternative Splicing; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005091:Exons; D006367:HeLa Cells; D006801:Humans; D009223:Myotonic Dystrophy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D055503:Protein Multimerization; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D019680:Trinucleotide Repeat Expansion
chemical_list: C493663:MBNL1 protein, human; D020033:Protein Isoforms; D016601:RNA-Binding Proteins