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Proc Natl Acad Sci U S A. 2017 Nov 7;114(45):11950-11955. doi: 10.1073/pnas.1715229114. Epub 2017 Oct 23.

Requirement of the fusogenic micropeptide myomixer for muscle formation in zebrafish.

Shi J1,2, Bi P1,2,3, Pei J4, Li H1,2,3, Grishin NV4,5, Bassel-Duby R1,2,3, Chen EH6,2, Olson EN6,2,3.

Author information

1
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
2
Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390.
3
Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390.
4
Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390.
5
Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, TX 75390.
6
Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390; Elizabeth.Chen@utsouthwestern.edu Eric.Olson@utsouthwestern.edu.

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.

KEYWORDS:

fusogenic; micropeptide; myogenesis; myomaker; zebrafish

PMID:
29078404
PMCID:
PMC5692600
DOI:
10.1073/pnas.1715229114
[Indexed for MEDLINE]
Free PMC Article

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