Cell-cell signaling is a major strategy that vertebrate embryos employ to control their development. We are interested in the mechanistic understanding of a major signaling pathway mediated by Wnts in the control of vertebrate embryonic development, in particular, limb development and skeletal morphogeneis. Early in limb development, signaling molecules which include the Wnt family members determine where and when the late structures, i.e., 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 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. Apart from Wnt signlaing pathways, other signaling pathways such PTHrP also plays a crtical role in regulating chondrocyte hypertophy, a process required for endochondral bone formation. To understand the molecular mechanism whereby Wnt signaling regulates chondrocyte hypertrophy and maturation, in the past year, we have investigated the interplay between signaling pathways of Wnt and PTHrP in controlling chondrocyte hypertrophy through analyzing mutant mice in which Wnt and PTHrP signaling components are either inactivated or ectopically expressed, we have uncovered that PTHrP signaling acts downstream of Wnt signlaing in regulating chondrocyte hypetrophy. Furthermore, we found that Wnt signlaing regulates the final maturation of hypertrophic chondrocytes independently of PTHrP signaling.

Agency
National Institute of Health (NIH)
Institute
National Human Genome Research Institute (NHGRI)
Type
Intramural Research (Z01)
Project #
1Z01HG000187-08
Application #
7734880
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2008
Total Cost
$1,023,617
Indirect Cost
Name
National Human Genome Research Institute
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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