The long tendons of the limb extend from muscles that reside in the zeugopod (arm/leg) to their skeletal insertions in the autopod (paw). How these connections are established along the length of the limb remains unknown. In this study, we show that limb tendons are formed in modular units that combine to form a functional contiguous structure; in muscle-less limbs, tendons develop in the autopod but do not extend into the zeugopod, and in the absence of limb cartilage, the zeugopod segments of tendons develop despite the absence of tendons in the autopod. Analyses of cell lineage and proliferation further indicate that distinct mechanisms govern growth of autopod and zeugopod tendon segments. To elucidate the integration of these autopod and zeugopod developmental programs, we reexamined early tendon development. At E12.5, muscles extend across the full length of a very short zeugopod and connect through short anlagen of tendon progenitors at the presumptive wrist to their respective autopod tendon segment, thereby initiating musculoskeletal integration. Zeugopod tendon segments are subsequently generated by proximal elongation of the wrist tendon anlagen, in parallel with skeletal growth, underscoring the dependence of zeugopod tendon development on muscles for tendon anchoring. Moreover, a subset of extensor tendons initially form as fused structures, due to initial attachment of their respective wrist tendon anlage to multiple muscles. Subsequent individuation of these tendons depends on muscle activity. Collectively, these results establish an integrated model for limb tendon development that we propose as a framework for future analyses of tendon and musculoskeletal phenotypes.
Musculoskeletal integration at the wrist underlies modular development of limb tendons
Currently Viewing Accepted Manuscript - Newer Version Available
Alice H. Huang, Timothy J. Riordan, Brian Pryce, Jennifer L. Weibel, Spencer S. Watson, Fanxin Long, Veronique Lefebvre, Brian D. Harfe, H. Scott Stadler, Haruhiko Akiyama, Sara F. Tufa, Douglas R. Keene, Ronen Schweitzer; Musculoskeletal integration at the wrist underlies modular development of limb tendons. Development 2015; dev.122374. doi: https://doi.org/10.1242/dev.122374
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