Abstract
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 lamininβ1 or lamininγ1 contrast with later dystrophic phenotypes in lamininα2 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.
Highlights
Muscle specification and morphogenesis during early development are critical for normal muscle physiology
Using a vertebrate model organism, the zebrafish, we find that single round myoblasts elongate to span the entire width of the myotome prior to fusion
Myotube formation involves boundary capture, where the ends of muscle fibers anchor themselves to the myotome boundary and stop elongating
Summary
Muscle specification and morphogenesis during early development are critical for normal muscle physiology. Most of the musculature is derived from somites [1,2,3]. Somites are segmentally reiterated structures delineated by somite boundaries. A portion of the somite gives rise to skeletal muscle fibers that comprise the myotome. The terminal ends of myotomal muscle fibers attach to somite boundaries, which become myotome boundaries. Myotome boundaries give rise to the myotendinous junction (MTJ) [4]
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