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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: 1.36). 09/2003; 3(4):459-62. DOI: 10.1016/S1567-133X(03)00064-4
Source: PubMed

ABSTRACT 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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    • "Expression was also strongly detected in the head. At H&H stage 18, MBNL1 expression continues in the developing heart and head, and is also seen in the forming limb buds (Figure 1B), consistent with reports from the mouse (Kanadia et al., 2003). "
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    • "The expression patterns of mouse Mbnl genes are similar to those in human (Kanadia et al., 2003b). Current data suggest that MBNL1 and MBNL3 may have opposing functions. "
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    ABSTRACT: Muscleblind-like (MBNL) proteins are a family of RNA-binding proteins that participate in the regulation of tissue-specific alternative splicing. Misregulation of MBNL activity in humans leads to pathogenesis. Here, we report upon the identification and characterization of three muscleblind-like genes in zebrafish (zmbnl1, zmbnl2 and zmbnl3). Alternative splicing of the three zmbnl primary transcripts gives rise to at least four protein isoforms for zmbnl1, four for zmbnl2 and five for zmbnl3, respectively. All of the zmbnl proteins contain the characteristic CCCH zinc fingers required for RNA binding. In addition, several structural motifs, including a C-terminal Ser/Thr-rich region, are conserved among Mbnl orthologs in vertebrates, but not invertebrates. These genes are broadly expressed in most adult tissues. However, the relative expression levels of specific spliceforms vary across different tissues. During embryogenesis, zmbnl1 and zmbnl2 are both maternally and zygotically expressed. In contrast, zmbnl3 transcripts are not detected until the late pharyngula stage. Our results reveal the expression pattern of various mbnl spliceforms for the first time and suggest that they may play specific roles during fish development.
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    • "There are three muscleblind paralogs in human, named MBNL1–3. Of the three human MBNL proteins, MBNL1 and MBNL2 are more abundant and have been shown to colocalize with CUG and CCUG repeats in the nucleus, forming nuclear foci in both DM1 and DM2 (Miller et al. 2000; Mankodi et al. 2001, 2003; Fardaei et al. 2002; Kanadia et al. 2003b; Jiang et al. 2004; Ho et al. 2005b; Lin et al. 2006). All three muscleblind proteins are similar in sequence and appear to have similar functions, as they can regulate alternative splicing in tissue culture (Ho et al. 2004; Dansithong et al. 2005; Paul et al. 2006). "
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    ABSTRACT: Myotonic dystrophy (DM) is a genetic disorder with multisystemic symptoms that is caused by expression (as RNA) of expanded repeats of CTG or CCTG in the genome. It is hypothesized that the RNA splicing factor muscleblind-like (MBNL) is sequestered to the expanded CUG or CCUG RNAs. Mislocalization of MBNL results in missplicing of a subset of pre-mRNAs that are linked to the symptoms found in DM patients. We demonstrate that MBNL can bind short structured CUG and CCUG repeats with high affinity and specificity. Only 6 base pairs are necessary for MBNL binding: two pyrimidine mismatches and four guanosine-cytosine base pairs in a stem. MBNL also has a preference for pyrimidine mismatches, but many other mismatches are tolerated with decreased affinity. We also demonstrate that MBNL binds the helical region of a stem-loop in the endogenous pre-mRNA target, the cardiac troponin T (cTNT) pre-mRNA. The stem-loop contains two mismatches and resembles both CUG and CCUG repeats. In vivo splicing results indicate that MBNL-regulated splicing is dependent upon the formation of stem-loops recognized by MBNL. These results suggest that MBNL may bind all of its RNA substrates, both normal and pathogenic, as structured stem-loops containing pyrimidine mismatches.
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