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. Here, we show that mouse 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 indicate that distinct mechanisms govern the growth of autopod and zeugopod tendon segments. To elucidate the integration of these autopod and zeugopod developmental programs, we re-examined 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. These results establish an integrated model for limb tendon development that provides a framework for future analyses of tendon and musculoskeletal phenotypes.

Summary The muscles that govern hand motion are composed of extrinsic muscles that reside within the forearm and intrinsic muscles that reside within the hand. We find that the extrinsic muscles of the flexor digitorum superficialis (FDS) first differentiate as intrinsic muscles within the hand and then relocate as myofibers to their final position in the arm. This unique translocation of differentiated myofibers across a joint is dependent on muscle contraction and muscle-tendon attachment. Interestingly, the intrinsic flexor digitorum brevis (FDB) muscles of the foot are identical to the FDS in tendon pattern and delayed developmental timing, but undergo limited muscle translocation, providing strong support for evolutionary homology between the FDS and FDB muscles. We propose that the intrinsic FDB pattern represents the original tetrapod limb and translocation of the muscles to form the FDS is a mammalian evolutionary addition.

No abstract

The range and precision of limb movements are dependent on the specific patterns of muscles and tendons. To facilitate analyses of tendon and muscle phenotypes we compiled a description of these tissues in the forelimb of developing mouse embryos. Individual tendons, muscles, and ligaments were annotated in a series of transverse sections through the forelimb of an embryo at day 18.5 of embryonic development (E18.5). Transverse sections present a distinctive and highly reproducible pattern of the muscles and tendons at different limb levels that can be used as a simple reference in analyses of mutant phenotypes. A comparable set of sections from an embryo at E14.5 was included to highlight structural features that change during the maturation of the musculoskeletal system. The ability to define the precise position of transverse sections along the proximal-distal axis of the limb may also be useful in studies of other features in developing limbs. Developmental Dynamics 238:693-700, 2009.