Abstract
Previous studies have shown that miR-203 is a skin-specific microRNA (miRNA) with a profound role in skin cell differentiation. However, emerging microarray and deep sequencing data revealed that miR-203 is also expressed in embryonic skeletal muscle and myoblasts. In this study, we found that miR-203 was transiently upregulated in chicken embryos on days 10 to 16 (E10–E16) and was sharply downregulated and even not expressed after E16 in chicken embryonic skeletal muscle. Histological profiles and weight variations of embryo skeletal muscle revealed that miR-203 expression is correlated with muscle development. In vitro experiments showed that miR-203 exhibited downregulated expression during myoblast differentiation into myotubes. miR-203 overexpression inhibited myoblast proliferation and differentiation, whereas its loss-of-function increased myoblast proliferation and differentiation. During myogenesis, miR-203 can target and inhibit the expression of c-JUN and MEF2C, which were important for cell proliferation and muscle development, respectively. The overexpression of c-JUN significantly promoted myoblast proliferation. Conversely, knockdown of c-JUN by siRNA suppressed myoblast proliferation. In addition, the knockdown of MEF2C by siRNA significantly inhibited myoblast differentiation. Altogether, these data not only suggested that the expression of miR-203 is transitory during chicken skeletal muscle development but also showed a novel role of miR-203 in inhibiting skeletal muscle cell proliferation and differentiation by repressing c-JUN and MEF2C, respectively.
Highlights
MEF2C belongs to the myocyte enhancer factor 2 family (MEF2) comprising four members encoded by different genes—MEF2A, B, C and D.8
Mouse bearing a c-JUN null mutation will die at mid-gestation because of the retardation of cell proliferation, and the primary fibroblasts from this c-JUN null embryo show greatly reduced growth rates in culture.[20] c-JUN gain-and-loss-of-function reveals that the positive role of c-JUN in cell cycle progression is p53 dependent.[21] p53 is an important tumour suppressor gene that has an inhibitory role in cell cycle progression through its target gene, the cyclin-dependent kinase inhibitor p21.22 c-JUN inhibits p53 transcription by direct binding to a
We explored the functional significance of miR-203 in chicken skeletal muscle development and found that miR-203 could repress primary myoblast proliferation and differentiation by directly inhibiting c-JUN and MEF2C expression, respectively
Summary
MEF2C belongs to the myocyte enhancer factor 2 family (MEF2) comprising four members encoded by different genes—MEF2A, B, C and D.8 In Drosophila, mutations in MEF2 result in a complete loss of muscle differentiation,[9,10,11] and more than 200 target genes and over 650 regions of the genome are bound by MEF2 during myogenesis,[12] demonstrating its central role in muscle development. Several miRNAs, miR-1, miR-206 and miR-133, were found to participate in muscle development.[23,24] These myogenic miRNAs (myomiRs) regulate muscle development by fine-tuning gene expression or acting as binary on/off switches.[25] To better understand this regulation, we previously counted all of the verified miRNAs involved in skeletal muscle differentiation.[26] Through interactions with many myogenic regulators, these miRNAs have important roles in the regulation of skeletal muscle differentiation None of these miRNAs were found in a chicken embryo study, which is a classic model for development research. Our results confirm and illustrate that a skin-specific miRNA can express and function in skeletal muscle development
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