title: Dual roles of Wnt signaling during chondrogenesis in the chicken limb.
abstract: Long bones of the appendicular skeleton are formed from a cartilage template in a process known as endochondral bone development. Chondrocytes within this template undergo a progressive program of differentiation from proliferating to postmitotic prehypertrophic to hypertrophic chondrocytes, while mesenchymal cells immediately surrounding the early cartilage template form the perichondrium. Recently, members of the Wnt family of secreted signaling molecules have been implicated in regulating chondrocyte differentiation. We find that Wnt-5a, Wnt-5b and Wnt-4 genes are expressed in chondrogenic regions of the chicken limb: Wnt-5a is expressed in the perichondrium, Wnt-5b is expressed in a subpopulation of prehypertrophic chondrocytes and in the outermost cell layer of the perichondrium, and Wnt-4 is expressed in cells of the joint region. Misexpression experiments demonstrate that two of these Wnt molecules, Wnt-5a and Wnt-4, have opposing effects on the differentiation of chondrocytes and that these effects are mediated through divergent signaling pathways. Specifically, Wnt-5a misexpression delays the maturation of chondrocytes and the onset of bone collar formation, while Wnt-4 misexpression accelerates these two processes. Misexpression of a stabilized form of beta-catenin also results in accelerated chondrogenesis, suggesting that a beta-catenin/TCF-LEF complex is involved in mediating the positive regulatory effect of Wnt-4. A number of the genes involved in Wnt signal tranduction, including two members of the Frizzled gene family, which are believed to encode Wnt-receptors, show very dynamic and distinct expression patterns in cartilaginous elements of developing chicken limbs. Misexpression of putative dominant-negative forms of the two Frizzled proteins results in severe shortening of the infected cartilage elements due to a delay in chondrocyte maturation, indicating that an endogenous Wnt signal does indeed function to promote chondrogenic differentiation.
authors.affiliation: Harvard Medical School, Department of Genetics, Boston, Massachusetts 02115, USA.
authors.forename: C
authors.initials: C
authors.lastname: Hartmann
authors.forename: C J
authors.initials: CJ
authors.lastname: Tabin
mesh_terms: D000818:Animals; D001846:Bone Development / Q000235:genetics; D001842:Bone and Bones / Q000002:abnormalities; D002454:Cell Differentiation / Q000235:genetics; D002642:Chick Embryo; D019902:Chondrocytes / Q000378:metabolism; D020219:Chondrogenesis / Q000502:physiology*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005121:Extremities / Q000196:embryology*; D051157:Frizzled Receptors; D018507:Gene Expression Regulation, Developmental; D005799:Genes, Dominant; D051821:Lymphoid Enhancer-Binding Factor 1; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled; D017981:Receptors, Neurotransmitter / Q000235:genetics / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D060528:Wnt4 Protein; D051176:beta Catenin
chemical_list: D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; C489740:FZD1 protein, human; D051157:Frizzled Receptors; D051821:Lymphoid Enhancer-Binding Factor 1; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D017981:Receptors, Neurotransmitter; D015534:Trans-Activators; D014157:Transcription Factors; C555581:WNT4 protein, human; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D060528:Wnt4 Protein; D051176:beta Catenin