Wnt7b activates canonical signaling in epithelial and vascular smooth muscle cells through interactions with Fzd1, Fzd10, and LRP5.
Wnt7b is a Wnt ligand that has been demonstrated to play critical roles in several developmental processes, including lung airway and vascular development and chorion-allantois fusion during placental development. Wnt signaling involves the binding of Wnt ligands to cell surface receptors of the frizzled family and coreceptors of the LRP5/6 family. However, little is known of the ligand-receptor specificity exhibited by different Wnts, Fzds, and LRPs in Wnt signaling. Expression analysis of Fzds and LRP5/6 in the developing lung and vasculature showed that Fzd1, -4, -7, and -10 and LRP5/6 are expressed in tissue-specific patterns during lung development. Fzd1, -4, and -7 are expressed primarily in the developing lung mesenchyme, and Fzd10 is expressed in airway epithelium. LRP5 and LRP6 are expressed in airway epithelium during lung development, whereas LRP5 but not LRP6 expression is observed in the muscular component of large blood vessels, including the aorta. Cell transfection studies demonstrate that Wnt7b can activate the canonical Wnt pathway but not the noncanonical Wnt pathway in a cell-specific manner. Biochemical analysis demonstrates that Wnt7b can bind to Fzd1 and -10 on the cell surface and cooperatively activate canonical Wnt signaling with these receptors in the presence of LRP5. Together, these data demonstrate that Wnt7b signals through Fzd1 and -10 and LRP5 and implicate these Wnt coreceptors in the regulation of lung airway and vascular development.
Wang
Zhishan
Z
Department of Medicine, University of Pennsylvania, 956 BRB II/III, 421 Curie Blvd., Philadelphia, PA 19104, USA.
Shu
Weiguo
W
Lu
Min Min
MM
Morrisey
Edward E
EE
D000818:Animals; D002460:Cell Line; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000502:physiology; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology*; D051157:Frizzled Receptors; D020869:Gene Expression Profiling; D017930:Genes, Reporter; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism*; D006321:Heart / Q000033:anatomy & histology / Q000254:growth & development; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D026502:LDL-Receptor Related Proteins / Q000235:genetics / Q000378:metabolism*; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D008168:Lung / Q000033:anatomy & histology / Q000254:growth & development; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000254:growth & development; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000502:physiology*; D011506:Proteins / Q000235:genetics / Q000378:metabolism; 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*; D015398:Signal Transduction / Q000502:physiology*; D051153:Wnt Proteins
C402930:FZD4 protein, human; D051157:Frizzled Receptors; C489739:Fzd1 protein, mouse; C492388:Fzd10 protein, mouse; C498581:Fzd4 protein, mouse; D006023:Glycoproteins; D026502:LDL-Receptor Related Proteins; C555482:LRP5 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; C555483:Lrp5 protein, mouse; D011506:Proteins; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D017981:Receptors, Neurotransmitter; D051153:Wnt Proteins; C095937:Wnt7b protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases