Regulation of Mef2c activity by alternative splicing in zebrafish muscle development

Teleost fish possess two Mef2c gene paralogues: mef2ca and mef2cb. In zebrafish, Danio rerio, the Mef2cs proteins function to promote cardiomyogenic differentiation and myofibrilogenesis in nascent skeletal muscle fibers. In mouse and human, an array of MEF2C proteins are generated by alternative splicing (AS), yet specific functions have not been ascribed to each isoform in vivo. We found that the transcripts of zebrafish mef2ca and mef2cb are alternatively spliced, the resulting splice variants have differing biological activity. Among the two mef2c paralogues, mef2ca is more abundantly expressed in developing skeletal muscle and the splicing pattern of its transcript is tuned through zebrafish development. At 24 hours post fertilization (hpf), a stage when mef2ca activity is required for proper myogenesis, we found the expression of a highly active full length protein. At earlier stages mef2ca activity is attenuated by AS, indeed a high proportion of the mef2ca transcripts lack part of the transcriptional activation domain. We present evidence that the developmentally regulated AS of mef2ca transcripts is important for a correct development of the zebrafish embryos.