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Nucleic Acids Research Advance Access originally published online on August 31, 2009
Nucleic Acids Research 2009 37(19):6477-6490; doi:10.1093/nar/gkp681
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Nucleic Acids Research, 2009, Vol. 37, No. 19 6477-6490
© The Author(s) 2009. Published by Oxford University Press.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.5/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Molecular Biology

MBNL and CELF proteins regulate alternative splicing of the skeletal muscle chloride channel CLCN1

Yoshihiro Kino1,2, Chika Washizu1, Yoko Oma2, Hayato Onishi2, Yuriko Nezu2, Noboru Sasagawa2, Nobuyuki Nukina1 and Shoichi Ishiura2,*

1Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, 2-1, Hirosawa, Wako-shi, Saitama, 351-0198 and 2Department of Life Sciences, Graduate School of Arts and Sciences, the University of Tokyo, 3-8-1, Komaba, Meguro-ku, Tokyo, 153-8902, Japan

*To whom correspondence should be addressed. Tel: +81 3 5454 6739; Fax: +81 3 5454 6739; Email: cishiura{at}mail.ecc.u-tokyo.ac.jp

Received April 8, 2009. Revised July 30, 2009. Accepted August 3, 2009.

The expression and function of the skeletal muscle chloride channel CLCN1/ClC-1 is regulated by alternative splicing. Inclusion of the CLCN1 exon 7A is aberrantly elevated in myotonic dystrophy (DM), a genetic disorder caused by the expansion of a CTG or CCTG repeat. Increased exon 7A inclusion leads to a reduction in CLCN1 function, which can be causative of myotonia. Two RNA-binding protein families—muscleblind-like (MBNL) and CUG-BP and ETR-3-like factor (CELF) proteins—are thought to mediate the splicing misregulation in DM. Here, we have identified multiple factors that regulate the alternative splicing of a mouse Clcn1 minigene. The inclusion of exon 7A was repressed by MBNL proteins while promoted by an expanded CUG repeat or CELF4, but not by CUG-BP. Mutation analyses suggested that exon 7A and its flanking region mediate the effect of MBNL1, whereas another distinct region in intron 6 mediates that of CELF4. An exonic splicing enhancer essential for the inclusion of exon 7A was identified at the 5' end of this exon, which might be inhibited by MBNL1. Collectively, these results provide a mechanistic model for the regulation of Clcn1 splicing, and reveal novel regulatory properties of MBNL and CELF proteins.


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