Abstract
ABSTRACTSteinert disease, or myotonic dystrophy type 1 (DM1), is a multisystemic disorder caused by toxic noncoding CUG repeat transcripts, leading to altered levels of two RNA binding factors, MBNL1 and CELF1. The contribution of CELF1 to DM1 phenotypes is controversial. Here, we show that the Drosophila CELF1 family member, Bru-3, contributes to pathogenic muscle defects observed in a Drosophila model of DM1. Bru-3 displays predominantly cytoplasmic expression in muscles and its muscle-specific overexpression causes a range of phenotypes also observed in the fly DM1 model, including affected motility, fiber splitting, reduced myofiber length and altered myoblast fusion. Interestingly, comparative genome-wide transcriptomic analyses revealed that Bru-3 negatively regulates levels of mRNAs encoding a set of sarcomere components, including Actn transcripts. Conversely, it acts as a positive regulator of Actn translation. As CELF1 displays predominantly cytoplasmic expression in differentiating C2C12 myotubes and binds to Actn mRNA, we hypothesize that it might exert analogous functions in vertebrate muscles. Altogether, we propose that cytoplasmic Bru-3 contributes to DM1 pathogenesis in a Drosophila model by regulating sarcomeric transcripts and protein levels.
Highlights
IntroductionThe finding that 75% of human disease-related genes have functional orthologs in the fruit fly (Rubin et al, 2000) drove the development of Drosophila models for inherited disorders, including neuromuscular diseases (Chartier et al, 2006; Shcherbata et al, 2007; Garcia-Lopez et al, 2008) such as myotonic dystrophy type 1 (DM1) (de Haro et al, 2006; Yu et al, 2011; Picchio et al, 2013)
The reverse balance of muscleblind-like 1 (MBNL1) and CELF1 in DM1 leads to the mis-splicing of these pre-mRNAs, collectively explaining myotonia, diabetes and reduced myocardial function manifested in patients
Aret/Bru which is known to be expressed in a subset of adult muscles (Oas et al, 2014; Spletter et al, 2015) is not expressed in Drosophila larval muscles as shown by immunostaining (Fig. S1B,C), making it unlikely that it is a functional CELF1 ortholog
Summary
The finding that 75% of human disease-related genes have functional orthologs in the fruit fly (Rubin et al, 2000) drove the development of Drosophila models for inherited disorders, including neuromuscular diseases (Chartier et al, 2006; Shcherbata et al, 2007; Garcia-Lopez et al, 2008) such as myotonic dystrophy type 1 (DM1) (de Haro et al, 2006; Yu et al, 2011; Picchio et al, 2013). It is well accepted that in muscle cells, mutated DMPK transcripts with large CUG expansion form secondary structures (Mooers et al, 2005) able to sequester the muscleblind-like 1 (MBNL1) splicing factor into foci within nuclei (Taneja et al, 1995; Davis et al, 1997). The reverse balance of MBNL1 and CELF1 in DM1 leads to the mis-splicing of these pre-mRNAs, collectively explaining myotonia, diabetes and reduced myocardial function manifested in patients. Some other transcripts, such as alpha-actinin (Actn1-4) (Suzuki et al, 2002), MYH14 (Rinaldi et al, 2012) or Tau (MAPT) (Dhaenens et al, 2011) have been shown to be mis-spliced by CELF1 in DM1. CELF1 accumulation in DM1 patients can lead to various alterations in transcript processing
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