期刊
EMBO JOURNAL
卷 23, 期 15, 页码 3103-3112出版社
WILEY
DOI: 10.1038/sj.emboj.7600300
关键词
alternative splicing; CELF proteins; CUG-BP1; muscleblind; myotonic dystrophy
资金
- NHLBI NIH HHS [R01 HL045565, HL45565] Funding Source: Medline
- NIAMS NIH HHS [R01 AR046799, R01 AR045653, AR46799, AR45653] Funding Source: Medline
- NINDS NIH HHS [NS48843, P50 NS048843, U54 NS048843] Funding Source: Medline
Although the muscleblind (MBNL) protein family has been implicated in myotonic dystrophy (DM), a specific function for these proteins has not been reported. A key feature of the RNA-mediated pathogenesis model for DM is the disrupted splicing of specific pre-mRNA targets. Here we demonstrate that MBNL proteins regulate alternative splicing of two pre-mRNAs that are misregulated in DM, cardiac troponin T (cTNT) and insulin receptor (IR). Alternative cTNT and IR exons are also regulated by CELF proteins, which were previously implicated in DM pathogenesis. MBNL proteins promote opposite splicing patterns for cTNT and IR alternative exons, both of which are antagonized by CELF proteins. CELF- and MBNL-binding sites are distinct and regulation by MBNL does not require the CELF- binding site. The results are consistent with a mechanism for DM pathogenesis in which expanded repeats cause a loss of MBNL and/or gain of CELF activities, leading to misregulation of alternative splicing of specific pre-mRNA targets.
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