The long-term objective of this study is to provide insight into mechanisms of pathology in the spine through an understanding of signals involved in the formation of the axial skeleton as well as in the maintenance of tissue structure and function in the adult. We propose that signaling through Tgfbr2 regulates both the development of the axial skeleton and the maintenance of tissues in the adult spine. Members of the TGF-b superfamily are secreted signaling proteins that regulate many aspects of development and tissue homeostasis including growth, patterning, and cellular differentiation. Polymorphisms and mutations in human Tgfb genes have been associated with pathology in the adult spine. Previously, we generated transgenic mice that express a dominant-negative mutation of the TGF-B Type II receptor in post-natal skeletal tissue. The mice demonstrated a progressive skeletal disease with pathology resembling that observed in human spondyloarthropathies. We also recently showed that deletion of the TGF-b type II receptor in Col2a expressing tissue results in alterations in the development of the axial skeleton including failures in the formation of the vertebrae and intervertebral discs. The results together suggest TGF-b has an important role in regulating both embryonic development of the axial skeleton and tissue homeostasis in the adult spine, however, the mechanistic basis of TGF-b action in the axial skeleton is not known. We propose to address this issue using genetically altered mouse and primary cell culture models. We will test the following specific hypotheses: 1) Signaling through Tgfbr2 mediates development of the vertebrae by regulating the expansion of the sclerotome. 2) Signaling through Tgfbr2 mediates the development of dorsal vertebral structures by regulating dorsal migration of sclerotomal cells. 3) Tgfbr2 regulates the patterning of the sclerotome. 4A) Tgfbr2 directs differentiation of sclerotomal cells towards the annulus fibrosus phenotype. 4B) TGF-b regulates the formation and maintenance of the IVD by antagonizing BMP activity. Understanding how specific cellular differentiation pathways occur in the first place and how differentiation is maintained in the adult will provide a basis for repair and regeneration strategies in the spine.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Skeletal Biology Structure and Regeneration Study Section (SBSR)
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Tyree, Bernadette
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University of Alabama Birmingham
Anatomy/Cell Biology
Schools of Medicine
United States
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Cox, Megan K; Appelboom, Brittany L; Ban, Ga I et al. (2014) Erg cooperates with TGF-β to control mesenchymal differentiation. Exp Cell Res 328:410-8
Chang, Ching-Fang; Serra, Rosa (2013) Ift88 regulates Hedgehog signaling, Sfrp5 expression, and β-catenin activity in post-natal growth plate. J Orthop Res 31:350-6
Wang, Ying; Cox, Megan K; Coricor, George et al. (2013) Inactivation of Tgfbr2 in Osterix-Cre expressing dental mesenchyme disrupts molar root formation. Dev Biol 382:27-37
Wang, Ying; Serra, Rosa (2012) PDGF mediates TGFýý-induced migration during development of the spinous process. Dev Biol 365:110-7
Ramaswamy, Girish; Sohn, Philip; Eberhardt, Alan et al. (2012) Altered responsiveness to TGF-ýý results in reduced Papss2 expression and alterations in the biomechanical properties of mouse articular cartilage. Arthritis Res Ther 14:R49
Chang, C-F; Ramaswamy, G; Serra, R (2012) Depletion of primary cilia in articular chondrocytes results in reduced Gli3 repressor to activator ratio, increased Hedgehog signaling, and symptoms of early osteoarthritis. Osteoarthritis Cartilage 20:152-61
Sohn, Philip; Cox, Megan; Chen, Dongquan et al. (2010) Molecular profiling of the developing mouse axial skeleton: a role for Tgfbr2 in the development of the intervertebral disc. BMC Dev Biol 10:29
Serra, Rosa (2008) Role of intraflagellar transport and primary cilia in skeletal development. Anat Rec (Hoboken) 291:1049-61
Seo, Hwa-Seon; Serra, Rosa (2007) Deletion of Tgfbr2 in Prx1-cre expressing mesenchyme results in defects in development of the long bones and joints. Dev Biol 310:304-16