title: SOXC proteins amplify canonical WNT signaling to secure nonchondrocytic fates in skeletogenesis.
abstract: Canonical WNT signaling stabilizes β-catenin to determine cell fate in many processes from development onwards. One of its main roles in skeletogenesis is to antagonize the chondrogenic transcription factor SOX9. We here identify the SOXC proteins as potent amplifiers of this pathway. The SOXC genes, i.e., Sox4, Sox11, and Sox12, are coexpressed in skeletogenic mesenchyme, including presumptive joints and perichondrium, but not in cartilage. Their inactivation in mouse embryo limb bud caused massive cartilage fusions, as joint and perichondrium cells underwent chondrogenesis. SOXC proteins govern these cells cell autonomously. They replace SOX9 in the adenomatous polyposis coli-Axin destruction complex and therein inhibit phosphorylation of β-catenin by GSK3. This inhibition, a crucial, limiting step in canonical WNT signaling, thus becomes a constitutive event. The resulting SOXC/canonical WNT-mediated synergistic stabilization of β-catenin contributes to efficient repression of Sox9 in presumptive joint and perichondrium cells and thereby ensures proper delineation and articulation of skeletal primordia. This synergy may determine cell fate in many processes besides skeletogenesis.
authors.affiliation: Department of Cellular and Molecular Medicine, Orthopaedic and Rheumatologic Research Center, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195 lefebvv@ccf.org bhattap2@ccf.org.
authors.forename: Pallavi
authors.initials: P
authors.lastname: Bhattaram
authors.affiliation: Department of Cellular and Molecular Medicine, Orthopaedic and Rheumatologic Research Center, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Penzo-Méndez
authors.affiliation: Department of Cellular and Molecular Medicine, Orthopaedic and Rheumatologic Research Center, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kato
authors.affiliation: Department of Cellular and Molecular Medicine, Orthopaedic and Rheumatologic Research Center, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195.
authors.forename: Kaustav
authors.initials: K
authors.lastname: Bandyopadhyay
authors.affiliation: Department of Cellular and Molecular Medicine, Orthopaedic and Rheumatologic Research Center, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195.
authors.forename: Abhilash
authors.initials: A
authors.lastname: Gadi
authors.affiliation: Department of Pharmacology, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Makoto M
authors.initials: MM
authors.lastname: Taketo
authors.affiliation: Department of Cellular and Molecular Medicine, Orthopaedic and Rheumatologic Research Center, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195 lefebvv@ccf.org bhattap2@ccf.org.
authors.forename: Véronique
authors.initials: V
authors.lastname: Lefebvre
mesh_terms: D000818:Animals; D002356:Cartilage / Q000166:cytology / Q000196:embryology; D019902:Chondrocytes / Q000502:physiology; D053595:Embryonic Stem Cells / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008822:Mice, Transgenic; D010012:Osteogenesis; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D055550:Protein Stability; D055751:SOXC Transcription Factors / Q000502:physiology*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: C495267:CTNNB1 protein, mouse; D055751:SOXC Transcription Factors; D051176:beta Catenin; D038362:Glycogen Synthase Kinase 3