Distinct functions of alternatively spliced isoforms encoded by zebrafish mef2ca and mef2cb

Ganassi, M., Badodi, S., Polacchini, A., Baruffaldi, F., Battini, R., Hughes, S.M., Hinits, Y., Molinari, S.
Biochimica et biophysica acta. Gene regulatory mechanisms   1839(7): 559-70 (Journal)
Registered Authors
Hinits, Yaniv, Hughes, Simon M.
Mef2ca, Mef2cb, alternative splicing, development, skeletal muscle, zebrafish
MeSH Terms
  • Alternative Splicing/genetics
  • Animals
  • Cell Differentiation/genetics*
  • Gene Expression Regulation, Developmental
  • Glycoproteins/biosynthesis
  • Glycoproteins/genetics
  • Goosecoid Protein/biosynthesis
  • Goosecoid Protein/genetics
  • Intercellular Signaling Peptides and Proteins/biosynthesis
  • Intercellular Signaling Peptides and Proteins/genetics
  • MEF2 Transcription Factors/genetics*
  • Muscle Development/genetics*
  • Muscle Proteins/genetics*
  • Nodal Signaling Ligands/biosynthesis
  • Nodal Signaling Ligands/genetics
  • Protein Isoforms/genetics
  • RNA Splicing/genetics
  • Zebrafish/genetics
  • Zebrafish/growth & development
  • Zebrafish Proteins/biosynthesis
  • Zebrafish Proteins/genetics*
24844180 Full text @ BBA Gene Regulatory Mechanisms
In mammals, an array of MEF2C proteins are generated by alternative splicing (AS), yet specific functions have not been ascribed to each isoform. Teleost fish possess two MEF2C paralogues, mef2ca and mef2cb. In zebrafish, the Mef2cs function to promote cardiomyogenic differentiation and myofibrillogenesis in nascent skeletal myofibers. We found that zebrafish mef2ca and mef2cb are alternatively spliced in the coding exons 4-6 region and these splice variants differ in their biological activity. Of the two, mef2ca is more abundantly expressed in developing skeletal muscle, its activity is tuned through zebrafish development by AS. By 24 hpf, we found the prevalent expression of the highly active full length protein in differentiated muscle in the somites. The splicing isoform of mef2ca that lacks exon 5 (mef2ca 4-6), encodes a protein that has 50% lower transcriptional activity, and is found mainly earlier in development, before muscle differentiation. mef2ca transcripts including exon 5 (mef2ca 4-5-6) are present early in the embryo. Over-expression of this isoform alters the expression of genes involved in early dorso-ventral patterning of the embryo such as chordin, nodal related 1 and goosecoid, and induces severe developmental defects. AS of mef2cb generates a long splicing isoform in the exon 5 region (Mef2cbL) that predominates during somitogenesis. Mef2cbL contains an evolutionarily conserved domain derived from exonization of a fragment of intron 5, which confers the ability to induce ectopic muscle in mesoderm upon over-expression of the protein. Taken together, the data show that AS is a significant regulator of Mef2c activity.
Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes