Time-lapse analysis and mathematical characterization elucidate novel mechanisms underlying muscle morphogenesis

Snow, C.J., Goody, M., Kelly, M.W., Oster, E.C., Jones, R., Khalil, A., and Henry, C.A.
PLoS Genetics   4(10): e1000219 (Journal)
Registered Authors
Henry, Clarissa A., Jones, Robert, Oster, Emma
Muscle cells, Embryos, Morphogenesis, Muscle fibers, Precursor cells, Muscle biochemistry, Cell fusion, Zebrafish
MeSH Terms
  • Animals
  • Image Processing, Computer-Assisted*
  • Laminin/metabolism
  • Models, Theoretical*
  • Morphogenesis*
  • Muscle Fibers, Skeletal/chemistry
  • Muscle Fibers, Skeletal/metabolism
  • Muscle, Skeletal/chemistry
  • Muscle, Skeletal/embryology
  • Muscle, Skeletal/growth & development*
  • Muscle, Skeletal/metabolism
  • Zebrafish/embryology
  • Zebrafish/growth & development*
  • Zebrafish/metabolism
  • Zebrafish Proteins/metabolism
18833302 Full text @ PLoS Genet.
Skeletal muscle morphogenesis transforms short muscle precursor cells into long, multinucleate myotubes that anchor to tendons via the myotendinous junction (MTJ). In vertebrates, a great deal is known about muscle specification as well as how somitic cells, as a cohort, generate the early myotome. However, the cellular mechanisms that generate long muscle fibers from short cells and the molecular factors that limit elongation are unknown. We show that zebrafish fast muscle fiber morphogenesis consists of three discrete phases: short precursor cells, intercalation/elongation, and boundary capture/myotube formation. In the first phase, cells exhibit randomly directed protrusive activity. The second phase, intercalation/elongation, proceeds via a two-step process: protrusion extension and filling. This repetition of protrusion extension and filling continues until both the anterior and posterior ends of the muscle fiber reach the MTJ. Finally, both ends of the muscle fiber anchor to the MTJ (boundary capture) and undergo further morphogenetic changes as they adopt the stereotypical, cylindrical shape of myotubes. We find that the basement membrane protein laminin is required for efficient elongation, proper fiber orientation, and boundary capture. These early muscle defects in the absence of either lamininbeta1 or laminingamma1 contrast with later dystrophic phenotypes in lamininalpha2 mutant embryos, indicating discrete roles for different laminin chains during early muscle development. Surprisingly, genetic mosaic analysis suggests that boundary capture is a cell-autonomous phenomenon. Taken together, our results define three phases of muscle fiber morphogenesis and show that the critical second phase of elongation proceeds by a repetitive process of protrusion extension and protrusion filling. Furthermore, we show that laminin is a novel and critical molecular cue mediating fiber orientation and limiting muscle cell length.
Genes / Markers
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Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes