Early in vertebrate embryonic development, cell-cell signaling plays important roles. We are interested in the mechanistic understanding of Wnt and hedgehog signaling pathways in the control of vertebrate embryonic development, in particular, limb development and skeletal morphogeneis. Early in limb development, signaling molecules which include the Wnt and hedgehog family members determines where and when the late structures, ie, skeletal elements will form. Skeletal morphogeneis in the limb occurs through endochondral bone formation in which chondrocytes (they form the cartilage) and osteoblasts (they secrete bone matrix) are first differentiated from mesenchymal condensations. This is followed by sequential proliferation and maturation of both chondrocytes and osteoblasts, which are tightly regulated and coordinated to ensure proper morphogenesis of the skeletal system. Through analyzing mutant mice in which Wnt signaling components are either inactivated or ectopically expressed, we have found that Wnt5a, in contrast to many other Wnts, signal through a novel pathway to antagonize the canonic Wnt pathway in regulating embryonic development and possibly in suppressing tumor formation.In addition, we have found that several Wnt genes are expressed in overlapping and complementary patterns in the developing synovial joints, where beta-catenin protein levels and transcription activity were up-regulated. We demonstrated that that Wnt/ beta-catenin signaling pathway is both necessary and sufficient to induce early steps of synovial joint formation. Furthermore, we found that the Wnt/ beta-catenin signaling pathway also controls the differentiation of osteoblasts and chondrocytes from mesenchymal progenitor cells. Wnt/ beta-catenin signaling pathway is also essential in the regulation of chondrocyte hypertrophy. Our results indicate that by manupilating the strength of the Wnt/ beta-catenin signaling, it is now possible to direct the differentiation of progenitor cells and stem cells along only the chondrocyte or osteoblast lineage. Our research work demonstrated that the Wnt/ beta-catenin signaling pathway is a critical target for the therapeutic development of both osteoporosis and osteoarthritis.

Agency
National Institute of Health (NIH)
Institute
National Human Genome Research Institute (NHGRI)
Type
Intramural Research (Z01)
Project #
1Z01HG000187-05
Application #
7147960
Study Section
(GDRB)
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2005
Total Cost
Indirect Cost
Name
Human Genome Research
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Guo, Xizhi; Mak, Kinglun Kingston; Taketo, Makoto M et al. (2009) The Wnt/beta-catenin pathway interacts differentially with PTHrP signaling to control chondrocyte hypertrophy and final maturation. PLoS One 4:e6067
Topol, Lilia; Chen, Wen; Song, Hai et al. (2009) Sox9 inhibits Wnt signaling by promoting beta-catenin phosphorylation in the nucleus. J Biol Chem 284:3323-33
Al-Qattan, Mohammad M; Yang, Yingzi; Kozin, Scott H (2009) Embryology of the upper limb. J Hand Surg Am 34:1340-50
Yang, Yingzi (2009) Growth and patterning in the limb: signaling gradients make the decision. Sci Signal 2:pe3
Yang, Yingzi; Kozin, Scott H (2009) Cell signaling regulation of vertebrate limb growth and patterning. J Bone Joint Surg Am 91 Suppl 4:76-80
Nemeth, Michael J; Topol, Lilia; Anderson, Stacie M et al. (2007) Wnt5a inhibits canonical Wnt signaling in hematopoietic stem cells and enhances repopulation. Proc Natl Acad Sci U S A 104:15436-41
Mak, Kingston Kinglun; Chen, Miao-Hsueh; Day, Timothy F et al. (2006) Wnt/beta-catenin signaling interacts differentially with Ihh signaling in controlling endochondral bone and synovial joint formation. Development 133:3695-707
Day, Timothy F; Guo, Xizhi; Garrett-Beal, Lisa et al. (2005) Wnt/beta-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis. Dev Cell 8:739-50
Guo, Xizhi; Day, Timothy F; Jiang, Xueyuan et al. (2004) Wnt/beta-catenin signaling is sufficient and necessary for synovial joint formation. Genes Dev 18:2404-17
Topol, Lilia; Jiang, Xueyuan; Choi, Hosoon et al. (2003) Wnt-5a inhibits the canonical Wnt pathway by promoting GSK-3-independent beta-catenin degradation. J Cell Biol 162:899-908

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