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Analysis of exonic regions involved in nuclear localization, splicing activity, and dimerization of Muscleblind-like-1 isoforms.

The Journal of biological chemistry (2011-04-02)
Hélène Tran, Nathalie Gourrier, Camille Lemercier-Neuillet, Claire-Marie Dhaenens, Audrey Vautrin, Francisco José Fernandez-Gomez, Ludovic Arandel, Céline Carpentier, Hélène Obriot, Sabiha Eddarkaoui, Lucie Delattre, Edwige Van Brussels, Ian Holt, Glenn E Morris, Bernard Sablonnière, Luc Buée, Nicolas Charlet-Berguerand, Susanna Schraen-Maschke, Denis Furling, Isabelle Behm-Ansmant, Christiane Branlant, Marie-Laure Caillet-Boudin, Nicolas Sergeant
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.

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Sigma-Aldrich
Monoclonal Anti-β-Tubulin antibody produced in mouse, clone TUB 2.1, ascites fluid