Developmental expression of mouse muscleblind genes Mbnl1, Mbnl2, Mbnl3

Department of Molecular Genetics and Microbiology, Powell Gene Therapy Center, University of Florida, College of Medicine, 1600 SW Archer Road, Gainesville, FL 32610-0267, USA.
Gene Expression Patterns (Impact Factor: 1.38). 09/2003; 3(4):459-62. DOI: 10.1016/S1567-133X(03)00064-4
Source: PubMed


The RNA-mediated pathogenesis model for the myotonic dystrophies DM1 and DM2 proposes that mutant transcripts from the affected genes sequester a family of double-stranded RNA-binding factors, the muscleblind proteins MBNL1, MBNL2 and MBNL3, in the nucleus. These proteins are homologues of the Drosophila muscleblind proteins that are required for the terminal differentiation of muscle and photoreceptor tissues, and thus nuclear sequestration of the human proteins might impair their normal function in muscle and eye development and maintenance. To examine this model further, we analyzed the expression pattern of the mouse Mbnl1, Mbnl2, and Mbnl3 genes during embryonic development and compared muscleblind gene expression to Dmpk since the RNA pathogenesis model for DM1 requires the coordinate synthesis of mutant Dmpk transcripts and muscleblind proteins. Our studies reveal a striking overlap between the expression of Dmpk and the muscleblind genes during development of the limbs, nervous system and various muscles, including the diaphragm and tongue.

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    • "The muscleblind gene was originally described in Drosophila melanogaster, which possesses a single gene[18]. Subsequently, three homologs—muscleblind-like genes MBNL1, MBNL2, and MBNL3—were identified in humans and mice, in which they express mainly in skeletal muscle and the nervous system[15,17,19]. MBNL genes code for conserved RNA-binding proteins, which function as alternative splicing factors[16]. "
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    ABSTRACT: MicroRNAs (miRNAs), a class of single stranded, small (~22 nucleotides), non-coding RNAs, play an important role in muscle development. We focused on the role of the miR-30-5p family during bovine muscle development from previous high-throughput sequencing results and analyzed their expression profiles. MHC and MyoG mRNAs expression as well as their proteins were suppressed in differentiated C2C12 cells, suggesting the importance of miR-30-5p in muscle development. MBNL, the candidate target of miR-30-5p, is an alternative splicing regulation factor. MBNL1 and MBNL3 have opposite effects on muscle differentiation. Our results confirmed that miR-30a-5p and miR-30e-5p repress the expression of MBNL1, MBNL2 and MBNL3, whereas miR-30b-5p inhibits MBNL1 and MBNL2 expression. This provides direct evidence that MBNL expression can be flexibly regulated by miR-30-5p. Previous studies showed that MBNL1 promotes exon inclusion of two muscle-related genes (Trim55 and INSR). Through RNA splicing studies, we found that miR-30-5p had an effect on their alternative splicing, which means miR-30-5p via MBNL1 could be integrated into muscle signaling pathways in which INSR or Trim55 are located. In conclusion, miR-30-5p could inhibit muscle cell differentiation and regulate the alternative splicing of Trim55 and INSR by targeting MBNL. These results promote the understanding of the function of miRNAs in muscle development.
    Preview · Article · Jan 2016 · International Journal of Molecular Sciences
    • "Mammals possess three Mbnl genes (Fardaei et al. 2002). In mouse and human, MBNL1 and MBNL2 proteins are expressed across many tissues (brain, heart, muscle), whereas MBNL3 is mainly expressed in placenta (Squillace et al. 2002 ;Kanadia et al. 2003a), suggesting functional specialization. MBNL proteins contain two pairs of highly conserved zinc fi nger domains, which bind to pre-mRNA to regulate AS (Pascual et al. 2006). "
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    ABSTRACT: RNA-binding proteins (RBPs) are key players of posttranscriptional regulation occurring during normal tissue development. All tissues examined thus far have revealed the importance of RBPs in the regulation of complex networks involved in organ morphogenesis, maturation, and function. They are responsible for controlling tissue-specific gene expression by regulating alternative splicing, mRNA stability, translation, and poly-adenylation. The heart is the first organ form during embryonic development and is also the first to acquire functionality. Numerous remodeling processes take place during late cardiac development since fetal heart first adapts to birth and then undergoes a transition to adult functionality. This physiological remodeling involves transcriptional and posttranscriptional networks that are regulated by RBPs. Disruption of the normal regulatory networks has been shown to cause cardiomyopathy in humans and animal models. Here we review the complexity of late heart development and the current information regarding how RBPs control aspects of postnatal heart development. We also review how activities of RBPs are modulated adding complexity to the regulation of developmental networks.
    No preview · Article · Sep 2014 · Advances in Experimental Medicine and Biology
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    • "MBNL3 antagonizes muscle differentiation by promoting exclusion of the alternatively spliced β-exon of Myocyte enhancer factor 2D (Mef2D) [23] and also by the inhibition of myogenesis by maintaining myoblasts in a proliferative state [24], [25]. As a result of this regulation a negative correlation exists between MBNL1 and MBNL3 expression levels in muscle during development when MBNL3 is mainly detected during embryonic development, but also transiently during injury-induced adult skeletal muscle regeneration [13], [26]. MBNL1 and MBNL2 have a similar expression pattern in skeletal and heart muscle, kidney, liver, lung, intestine, brain and placenta. "
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    ABSTRACT: The phylogenetically conserved family of Muscleblind proteins are RNA-binding factors involved in a variety of gene expression processes including alternative splicing regulation, RNA stability and subcellular localization, and miRNA biogenesis, which typically contribute to cell-type specific differentiation. In humans, sequestration of Muscleblind-like proteins MBNL1 and MBNL2 has been implicated in degenerative disorders, particularly expansion diseases such as myotonic dystrophy type 1 and 2. Drosophila muscleblind was previously shown to be expressed in embryonic somatic and visceral muscle subtypes, and in the central nervous system, and to depend on Mef2 for transcriptional activation. Genomic approaches have pointed out candidate gene promoters and tissue-specific enhancers, but experimental confirmation of their regulatory roles was lacking. In our study, luciferase reporter assays in S2 cells confirmed that regions P1 (515 bp) and P2 (573 bp), involving the beginning of exon 1 and exon 2, respectively, were able to initiate RNA transcription. Similarly, transgenic Drosophila embryos carrying enhancer reporter constructs supported the existence of two regulatory regions which control embryonic expression of muscleblind in the central nerve cord (NE, neural enhancer; 830 bp) and somatic (skeletal) musculature (ME, muscle enhancer; 3.3 kb). Both NE and ME were able to boost expression from the Hsp70 heterologous promoter. In S2 cell assays most of the ME enhancer activation could be further narrowed down to a 1200 bp subregion (ME.3), which contains predicted binding sites for the Mef2 transcription factor. The present study constitutes the first characterization of muscleblind enhancers and will contribute to a deeper understanding of the transcriptional regulation of the gene.
    Full-text · Article · Mar 2014 · PLoS ONE
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