title: TMJ development and growth require primary cilia function.
abstract: Primary cilia regulate limb and axial skeletal formation and hedgehog signaling, but their roles in temporomandibular joint (TMJ) development are unknown. Thus, we created conditional mouse mutants deficient in ciliary transport protein Kif3a in cartilage. In post-natal wild-type mice, primary cilia were occasionally observed on the superior, inferior, or lateral side of condylar cells. Cilia were barely detectable in mutant chondrocytes but were evident in surrounding tissues, attesting to the specificity of chondrocyte Kif3a ablation. Mutant condyles from 3-month-old mice were narrow and flat along their antero-posterior and medio-lateral axes, were often fused with the articular disc, and displayed an irregular bony surface. The polymorphic layer in P15 mutants contained fewer Sox9-expressing chondroprogenitor cells because of reduced mitotic activity, and newly differentiated chondrocytes underwent precocious hypertrophic enlargement accompanied by early activation of Indian hedgehog (Ihh). Interestingly, there was excessive intramembranous ossification along the perichondrium, accompanied by local expression of the hedgehog receptor Patched-1 and up-regulation of Osterix and Collagen I. In summary, Kif3a and primary cilia are required for coordination of chondrocyte maturation, intramembranous bone formation, and chondrogenic condylar growth. Defects in these processes in Kif3a condylar cartilage are likely to reflect abnormal hedgehog signaling topography and dysfunction.
authors.affiliation: Department of Surgery, The Children's Hospital of Philadelphia Research Institute, 3615 Civic Center Boulevard, Abramson Research Center, 902 Philadelphia, PA 19104, USA.
authors.forename: T
authors.initials: T
authors.lastname: Kinumatsu
authors.forename: Y
authors.initials: Y
authors.lastname: Shibukawa
authors.forename: T
authors.initials: T
authors.lastname: Yasuda
authors.forename: M
authors.initials: M
authors.lastname: Nagayama
authors.forename: S
authors.initials: S
authors.lastname: Yamada
authors.forename: R
authors.initials: R
authors.lastname: Serra
authors.forename: M
authors.initials: M
authors.lastname: Pacifici
authors.forename: E
authors.initials: E
authors.lastname: Koyama
mesh_terms: D000818:Animals; D002358:Cartilage, Articular / Q000378:metabolism; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology; D020219:Chondrogenesis / Q000235:genetics; D002923:Cilia / Q000502:physiology*; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D006132:Growth Plate / Q000378:metabolism; D053823:Hedgehog Proteins / Q000235:genetics / Q000502:physiology*; D016547:Kinesins / Q000235:genetics / Q000502:physiology*; D008335:Mandibular Condyle / Q000254:growth & development*; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis; D009999:Ossification, Heterotopic / Q000235:genetics; D010012:Osteogenesis / Q000235:genetics; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology; D055758:SOX9 Transcription Factor / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction; D000076182:Sp7 Transcription Factor; D013704:Temporomandibular Joint / Q000254:growth & development*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology
chemical_list: D024042:Collagen Type I; D053823:Hedgehog Proteins; C490202:Kif3a protein, mouse; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D055758:SOX9 Transcription Factor; C527933:Sox9 protein, mouse; D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse; D014157:Transcription Factors; C514061:ihh protein, mouse; D016547:Kinesins