title: BMP-Smad4 signaling is required for precartilaginous mesenchymal condensation independent of Sox9 in the mouse.
abstract: Bone morphogenetic proteins (BMPs) regulate multiple aspects of skeletal development in vertebrates. Although exogenously applied BMPs can induce chondrogenesis de novo, the role and mechanism of physiologic BMP signaling during precartilaginous mesenchymal condensation is not well understood. By deleting the type I BMP receptors or the transcription factor Smad4 in the limb bud mesenchyme, we find that loss of BMP-Smad signaling abolishes skeletal development due to a failure in mesenchymal condensation. In the absence of Smad4, expression of Sox9, an essential transcription factor for chondrogenesis, initiates normally in the proximal mesenchyme of the limb bud, but fails to maintain its level or expand to the more distal territory at the later stages. However, forced-expression of Sox9 does not restore cartilage formation in the Smad4-deficeint embryo. In vitro micromass cultures show that the Smad4-deficient cells fail to condense in a cell-autonomous manner, even though they express several cell adhesion molecules either normally or even at a higher level. Thus, BMP-Smad signaling critically controls mesenchymal condensation to initiate skeletal development likely through a Sox9-independent mechanism.
authors: Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO 63110, United States; Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO 63110, United States.
authors: Joohyun
authors: J
authors: Lim
authors: Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States.
authors: Xiaolin
authors: X
authors: Tu
authors: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, United States.
authors: Kyunghee
authors: K
authors: Choi
authors: Department of Orthopaedic Surgery, Kyoto University, Kyoto, Japan.
authors: Haruhiko
authors: H
authors: Akiyama
authors: Department of Biologic and Materials Sciences, the University of Michigan School of Dentistry, Ann Arbor, MI 48109, United States.
authors: Yuji
authors: Y
authors: Mishina
authors: Department of Orthopaedic Surgery, Washington University School of Medicine, St. Louis, MO 63110, United States; Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, MO 63110, United States; Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, United States; Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, United States. Electronic address: flong@wustl.edu.
authors: Fanxin
authors: F
authors: Long
mesh_terms: D000818:Animals; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D005121:Extremities / Q000196:embryology*; D005455:Fluorescent Antibody Technique; D020287:In Situ Nick-End Labeling; D018878:Limb Buds / Q000196:embryology / Q000378:metabolism*; D008648:Mesoderm / Q000196:embryology*; D051379:Mice; D010012:Osteogenesis / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D055758:SOX9 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D051901:Smad4 Protein / Q000378:metabolism*
chemical_list: D017931:DNA Primers; D055758:SOX9 Transcription Factor; D051901:Smad4 Protein; C527933:Sox9 protein, mouse; D052005:Bone Morphogenetic Protein Receptors, Type I
keywords: Acvr1; Alk2; Alk3; Alk6; BMP; Bmpr1a; Bmpr1b; Cartilage; Mesenchymal condensation; Mouse; Smad4; Sox9
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