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.
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