The International Journal of Biochemistry & Cell Biology
Molecules in focusMicroRNAs 1, 133, and 206: Critical factors of skeletal and cardiac muscle development, function, and disease
Introduction
miRNAs are short (∼22 nucleotide), non-coding RNA molecules that influence gene expression, primarily post-transcriptionally. miRNAs negatively regulate gene expression through complementary base-pair binding of the miRNA “seed sequence” (nucleotides 2–7) to the 3′ untranslated region (UTR) of target mRNA, degrading or destabilizing the RNA message, or inhibiting protein translation, depending on the quantity of complimentary base-pair matches (Valencia-Sanchez et al., 2006) or the number of miRNA targeting sites within the 3′ UTR (Sandberg et al., 2008).
The muscle specific miR-1 and -206 are closely related in terms of expression and function, but differ based on chromosomal location, specific targets, and individual transcriptional activation. In general, both miR-1, found in both skeletal and cardiac muscle, and miR-206, specific for skeletal muscle, are shown to promote myoblast-to-myotube differentiation. By contrast, miR-133 promotes the proliferation of myoblasts, and inhibits their differentiation. miR-1-1 and miR-1-2 have identical mature nucleotide sequences, and miR-206 differs from this conserved miR-1 sequence by four nucleotides (Chen et al., 2006, Kim et al., 2006, Lagos-Quintana et al., 2002, Rosenberg et al., 2006). miR-133a-1 and miR-133a-2 share identical mature sequences, with miR-133b differing from this by a single nucleotide at the 3′ end (Chen et al., 2006, Niu et al., 2007). The miR-1-1/miR-133a-2 and the miR-206/miR-133b clusters are transcribed from non-coding regions on mouse chromosomes 2 and 1, respectively, while the miR-1-2/miR-133a-1 cluster is transcribed from an intronic region of the ubiquitously expressed E3 ubiquitin ligase gene Mib1 (Chen et al., 2006). Therefore, while these three related clusters have similar sequences and expression patterns, each not only has distinct targets and functions, but also must rely on their own promoters for muscle specific expression.
Section snippets
Development and function of cardiac and skeletal muscle
There are three primary muscle types; cardiac, skeletal, and smooth. All are derived from the embryonic mesoderm in vertebrates. Muscle development is a coordinated process which involves cellular proliferation, differentiation, migration, and cell death. Regulation of gene expression at both transcriptional and translational levels is crucial for morphologic development of muscle tissues. Among the three muscle types, cardiac and skeletal muscle are striated and terminally differentiated. They
Regulation and expression of miRNAs during muscle development
Whereas many miRNAs are ubiquitously expressed, some miRNAs are expressed in a tissue-specific manner. Investigation into transcriptional regulation of miRNAs in muscle development comes from, in part, recent studies of the miR-1 and miR-133 families. These studies indicate that expression of miRNA genes is under transcriptional regulation, similar to that of protein-coding genes. The bicistronic pairs of cardiac and skeletal muscle specific miR-1-1 and miR-133a-2 (clustered on mouse chromosome
Biological roles of miRNA in skeletal and cardiac muscle
To determine the global role of miRNAs in development, Bernstein and colleagues knocked out Dicer in mice, preventing the processing of miRNA precursors into functional mature molecules, and found that lethality occurs at embryonic day 7.5, with development likely halting in gastrulation (Bernstein et al., 2003). Further examination using tissue-specific Dicer deletion revealed that miRNAs are required for proper morphogenesis in skeletal muscle (O’Rourke et al., 2007) and cardiac muscle (Chen
Medical significance
As the characterization of specific miRNAs has increased exponentially in recent years, miRNAs have been implicated in a vast array of diseases, ranging from cancer to cardiovascular disorders. Many recent studies have documented dysregulation and abnormal expression of miRNAs in human patients and/or animal models for human disease. Given that miRNAs are also evolutionary conserved, a picture has emerged which points to a fundamental requirement of miRNAs in cardiac and skeletal muscle
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