Requirement of the fusogenic micropeptide myomixer for muscle formation in zebrafish

Jun Shi, Pengpeng Bi, Jimin Pei, Hui Li, Nick V Grishin, Rhonda S Bassel-Duby, Elizabeth Chen, Eric N Olson

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Skeletal muscle formation requires fusion of mononucleated myoblasts to form multinucleated myofibers. The muscle-specific membrane proteins myomaker and myomixer cooperate to drive mammalian myoblast fusion. Whereas myomaker is highly conserved across diverse vertebrate species, myomixer is a micropeptide that shows relatively weak cross-species conservation. To explore the functional conservation of myomixer, we investigated the expression and function of the zebrafish myomixer ortholog. Here we show that myomixer expression during zebrafish embryogenesis coincides with myoblast fusion, and genetic deletion of myomixer using CRISPR/Cas9 mutagenesis abolishes myoblast fusion in vivo. We also identify myomixer orthologs in other species of fish and reptiles, which can cooperate with myomaker and substitute for the fusogenic activity of mammalian myomixer. Sequence comparison of these diverse myomixer orthologs reveals key amino acid residues and a minimal fusogenic peptide motif that is necessary for promoting cell–cell fusion with myomaker. Our findings highlight the evolutionary conservation of the myomaker–myomixer partnership and provide insights into the molecular basis of myoblast fusion.

Original languageEnglish (US)
Pages (from-to)11950-11955
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number45
DOIs
StatePublished - Nov 7 2017

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Myoblasts
Zebrafish
Muscles
Clustered Regularly Interspaced Short Palindromic Repeats
Reptiles
Mutagenesis
Embryonic Development
Vertebrates
Membrane Proteins
Fishes
Skeletal Muscle
Amino Acids
Peptides

Keywords

  • Fusogenic
  • Micropeptide
  • Myogenesis
  • Myomaker
  • Zebrafish

ASJC Scopus subject areas

  • General

Cite this

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abstract = "Skeletal muscle formation requires fusion of mononucleated myoblasts to form multinucleated myofibers. The muscle-specific membrane proteins myomaker and myomixer cooperate to drive mammalian myoblast fusion. Whereas myomaker is highly conserved across diverse vertebrate species, myomixer is a micropeptide that shows relatively weak cross-species conservation. To explore the functional conservation of myomixer, we investigated the expression and function of the zebrafish myomixer ortholog. Here we show that myomixer expression during zebrafish embryogenesis coincides with myoblast fusion, and genetic deletion of myomixer using CRISPR/Cas9 mutagenesis abolishes myoblast fusion in vivo. We also identify myomixer orthologs in other species of fish and reptiles, which can cooperate with myomaker and substitute for the fusogenic activity of mammalian myomixer. Sequence comparison of these diverse myomixer orthologs reveals key amino acid residues and a minimal fusogenic peptide motif that is necessary for promoting cell–cell fusion with myomaker. Our findings highlight the evolutionary conservation of the myomaker–myomixer partnership and provide insights into the molecular basis of myoblast fusion.",
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AU - Bi, Pengpeng

AU - Pei, Jimin

AU - Li, Hui

AU - Grishin, Nick V

AU - Bassel-Duby, Rhonda S

AU - Chen, Elizabeth

AU - Olson, Eric N

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N2 - Skeletal muscle formation requires fusion of mononucleated myoblasts to form multinucleated myofibers. The muscle-specific membrane proteins myomaker and myomixer cooperate to drive mammalian myoblast fusion. Whereas myomaker is highly conserved across diverse vertebrate species, myomixer is a micropeptide that shows relatively weak cross-species conservation. To explore the functional conservation of myomixer, we investigated the expression and function of the zebrafish myomixer ortholog. Here we show that myomixer expression during zebrafish embryogenesis coincides with myoblast fusion, and genetic deletion of myomixer using CRISPR/Cas9 mutagenesis abolishes myoblast fusion in vivo. We also identify myomixer orthologs in other species of fish and reptiles, which can cooperate with myomaker and substitute for the fusogenic activity of mammalian myomixer. Sequence comparison of these diverse myomixer orthologs reveals key amino acid residues and a minimal fusogenic peptide motif that is necessary for promoting cell–cell fusion with myomaker. Our findings highlight the evolutionary conservation of the myomaker–myomixer partnership and provide insights into the molecular basis of myoblast fusion.

AB - Skeletal muscle formation requires fusion of mononucleated myoblasts to form multinucleated myofibers. The muscle-specific membrane proteins myomaker and myomixer cooperate to drive mammalian myoblast fusion. Whereas myomaker is highly conserved across diverse vertebrate species, myomixer is a micropeptide that shows relatively weak cross-species conservation. To explore the functional conservation of myomixer, we investigated the expression and function of the zebrafish myomixer ortholog. Here we show that myomixer expression during zebrafish embryogenesis coincides with myoblast fusion, and genetic deletion of myomixer using CRISPR/Cas9 mutagenesis abolishes myoblast fusion in vivo. We also identify myomixer orthologs in other species of fish and reptiles, which can cooperate with myomaker and substitute for the fusogenic activity of mammalian myomixer. Sequence comparison of these diverse myomixer orthologs reveals key amino acid residues and a minimal fusogenic peptide motif that is necessary for promoting cell–cell fusion with myomaker. Our findings highlight the evolutionary conservation of the myomaker–myomixer partnership and provide insights into the molecular basis of myoblast fusion.

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