EurekaMag.com logo
+ Site Statistics
References:
53,869,633
Abstracts:
29,686,251
+ Search Articles
+ Subscribe to Site Feeds
EurekaMag Most Shared ContentMost Shared
EurekaMag PDF Full Text ContentPDF Full Text
+ PDF Full Text
Request PDF Full TextRequest PDF Full Text
+ Follow Us
Follow on FacebookFollow on Facebook
Follow on TwitterFollow on Twitter
Follow on LinkedInFollow on LinkedIn

+ Translate

RBFOX1 cooperates with MBNL1 to control splicing in muscle, including events altered in myotonic dystrophy type 1



RBFOX1 cooperates with MBNL1 to control splicing in muscle, including events altered in myotonic dystrophy type 1



Plos One 9(9): E107324-E107324



With the goal of identifying splicing alterations in myotonic dystrophy 1 (DM1) tissues that may yield insights into targets or mechanisms, we have surveyed mis-splicing events in three systems using a RT-PCR screening and validation platform. First, a transgenic mouse model expressing CUG-repeats identified splicing alterations shared with other mouse models of DM1. Second, using cell cultures from human embryonic muscle, we noted that DM1-associated splicing alterations were significantly enriched in cytoskeleton (e.g. SORBS1, TACC2, TTN, ACTN1 and DMD) and channel (e.g. KCND3 and TRPM4) genes. Third, of the splicing alterations occurring in adult DM1 tissues, one produced a dominant negative variant of the splicing regulator RBFOX1. Notably, half of the splicing events controlled by MBNL1 were co-regulated by RBFOX1, and several events in this category were mis-spliced in DM1 tissues. Our results suggest that reduced RBFOX1 activity in DM1 tissues may amplify several of the splicing alterations caused by the deficiency in MBNL1.

(PDF emailed within 0-6 h: $19.90)

Accession: 055333642

Download citation: RISBibTeXText

PMID: 25211016

DOI: 10.1371/journal.pone.0107324



Related references

Mis-splicing of Tau exon 10 in myotonic dystrophy type 1 is reproduced by overexpression of CELF2 but not by MBNL1 silencing. Biochimica et Biophysica Acta 1812(7): 732-742, 2011

A flow cytometry-based screen identifies MBNL1 modulators that rescue splicing defects in myotonic dystrophy type I. Human Molecular Genetics 26(16): 3056-3068, 2017

Ribonuclear inclusions and MBNL1 nuclear sequestration do not affect myoblast differentiation but alter gene splicing in myotonic dystrophy type 2. Neuromuscular Disorders 19(5): 335-343, 2009

Altered mRNA splicing of the skeletal muscle ryanodine receptor and sarcoplasmic/endoplasmic reticulum Ca2+-ATPase in myotonic dystrophy type 1. Human Molecular Genetics 14(15): 2189-2200, 2005

Failure of MBNL1-dependent post-natal splicing transitions in myotonic dystrophy. Human Molecular Genetics 15(13): 2087-2097, 2006

A putative role of ribonuclear inclusions and MBNL1 in the impairment of gallbladder smooth muscle contractility with cholelithiasis in myotonic dystrophy type 1. Neuromuscular Disorders 18(8): 641-645, 2008

Altered mRNA splicing of dystrophin in type 1 myotonic dystrophy. Muscle & Nerve 36(2): 251-257, 2007

Muscle weakness in myotonic dystrophy associated with misregulated splicing and altered gating of Ca(V)1.1 calcium channel. Human Molecular Genetics 21(6): 1312-1324, 2012

A novel CUG(exp)·MBNL1 inhibitor with therapeutic potential for myotonic dystrophy type 1. Acs Chemical Biology 8(5): 1037-1043, 2014

Sequestration of MBNL1 in tissues of patients with myotonic dystrophy type 2. Neuromuscular Disorders 22(7): 604-616, 2012

Rbfox1 downregulation and altered calpain 3 splicing by FRG1 in a mouse model of Facioscapulohumeral muscular dystrophy (FSHD). Plos Genetics 9(1): E1003186-E1003186, 2013

Genome wide identification of aberrant alternative splicing events in myotonic dystrophy type 2. Plos One 9(4): E93983-E93983, 2015

Alternative splicing of human insulin receptor gene (INSR) in type I and type II skeletal muscle fibers of patients with myotonic dystrophy type 1 and type 2. Molecular and Cellular Biochemistry 380(1-2): 259-265, 2014

MBNL1 gene variants as modifiers of disease severity in myotonic dystrophy type 1. Journal of Neurology 260(4): 998-1003, 2013

Most expression and splicing changes in myotonic dystrophy type 1 and type 2 skeletal muscle are shared with other muscular dystrophies. Neuromuscular Disorders 24(3): 227-240, 2014