title: Musculoskeletal integration at the wrist underlies the modular development of limb tendons.
abstract: 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.
authors.affiliation: Research Division, Shriners Hospital for Children, Portland, OR 97209, USA.
authors.forename: Alice H
authors.initials: AH
authors.lastname: Huang
authors.affiliation: Research Division, Shriners Hospital for Children, Portland, OR 97209, USA.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Riordan
authors.affiliation: Research Division, Shriners Hospital for Children, Portland, OR 97209, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Pryce
authors.affiliation: Research Division, Shriners Hospital for Children, Portland, OR 97209, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Weibel
authors.affiliation: Research Division, Shriners Hospital for Children, Portland, OR 97209, USA.
authors.forename: Spencer S
authors.initials: SS
authors.lastname: Watson
authors.affiliation: Department of Orthopaedics, Washington University, St Louis, MO 63110, USA.
authors.forename: Fanxin
authors.initials: F
authors.lastname: Long
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Veronique
authors.initials: V
authors.lastname: Lefebvre
authors.affiliation: Department of Molecular Genetics and Microbiology and the Genetics Institute, University of Florida, Gainesville, FL 32611, USA.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Harfe
authors.affiliation: Research Division, Shriners Hospital for Children, Portland, OR 97209, USA.
authors.forename: H Scott
authors.initials: HS
authors.lastname: Stadler
authors.affiliation: Department of Orthopaedics, Gifu University, Gifu City, 501-1193, Japan.
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Akiyama
authors.affiliation: Research Division, Shriners Hospital for Children, Portland, OR 97209, USA.
authors.forename: Sara F
authors.initials: SF
authors.lastname: Tufa
authors.affiliation: Research Division, Shriners Hospital for Children, Portland, OR 97209, USA.
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Keene
authors.affiliation: Research Division, Shriners Hospital for Children, Portland, OR 97209, USA rsc@shcc.org.
authors.forename: Ronen
authors.initials: R
authors.lastname: Schweitzer
mesh_terms: D000818:Animals; D017209:Apoptosis; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D002356:Cartilage / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D005121:Extremities / Q000196:embryology*; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D049452:Green Fluorescent Proteins / Q000378:metabolism; D008662:Metacarpophalangeal Joint / Q000473:pathology; D051379:Mice; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D018482:Muscle, Skeletal / Q000196:embryology* / Q000378:metabolism; D010641:Phenotype; D055758:SOX9 Transcription Factor / Q000235:genetics; D013710:Tendons / Q000196:embryology* / Q000378:metabolism
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D049452:Green Fluorescent Proteins; D055758:SOX9 Transcription Factor; C503815:Scx protein, mouse; C527933:Sox9 protein, mouse
keywords: Limb; Musculoskeletal development; Tendon