Mis-splicing of Tau exon 10 in myotonic dystrophy type I is reproduced by overexpression of CELF2 but not by MBNL1 silencing

International audienceTau is the proteinaceous component of intraneuronal aggregates common to neurodegenerative diseases called Tauopathies, including myotonic dystrophy type I (DM1). In DM1, the presence of microtubule-associated protein Tau aggregates is associated with a mis-splicing of Tau. A toxic gain-of-function at the RNA level is a major etiological factor responsible for the mis-splicing of several transcripts in DM1. These are probably the consequence of a loss of MBNL1 function or gain of CELF1 splicing function. Whether these two dysfunctions occur together or separately, and whether all mis-splicing events in DM1 brain result from one or both of these dysfunctions remains unknown. Here, we analyzed the splicing of Tau exons 2 and 10 in the brain of DM1 patients. Two DM1 patients showed a mis-splicing of exon 10 whereas exon 2-inclusion was reduced in all DM1 patients. In order to determine the potential factors responsible for exon 10 mis-splicing, we studied the effect of the splicing factors MBNL1, CELF1, CELF2 and CELF4 or a dominant-negative CELF factor on Tau exon 10 splicing by ectopic expression or siRNA. Interestingly, the inclusion of Tau exon 10 is reduced by CELF2 whereas it is insensitive to the loss-of-function of MBNL1, CELF1 gain-of-function or a dominant-negative of CELF factor. Moreover, we observed an increased expression of CELF2 only in the brain of DM1 patients with a mis-splicing of exon 10. Taken together, our results indicate the occurrence of a mis-splicing event in DM1 that is neither induced by a loss of MBNL1 function nor a gain of CELF1 function, but is rather associated to CELF2 gain-of-function