title: Canonical Wnt signaling negatively regulates branching morphogenesis of the lung and lacrimal gland.
abstract: Key gene families such as FGFs and BMPs are important mediators of branching morphogenesis. To understand whether Wnt genes, and in particular, the canonical Wnt signaling pathway also function in the branching process, we have used a combination of experimental and genetic gain and loss of function approaches to perturb the levels of canonical Wnt signaling in two arborized structures, the lung and the lacrimal gland. Here, we show that the addition of Wnt3a conditioned medium or LiCl strongly represses growth and proliferation of the lung and lacrimal gland, a result that was confirmed in vivo using a dominant stable mutation of beta-catenin conditionally expressed in the lacrimal gland epithelium. In agreement with these data, knockdown of Wnt signaling with beta-catenin morpholinos results in a greater number of branches and increased cell proliferation. In addition, we show that canonical Wnt signaling is able to modulate the levels of Fgf10 and suppress BMP-induced proliferation in the lacrimal gland. Thus, canonical Wnt signaling negatively regulates branching morphogenesis providing a balance to FGFs and BMPs which positively regulate this process. This multilayered control of growth and proliferation ensures that branched structures attain the morphology required to function efficiently.
authors.affiliation: Memorial Sloan Kettering Cancer Center, Developmental Biology Program, 1275 York Avenue, New York, NY 10021, USA. c.dean@har.mrc.ac.uk
authors.forename: Charlotte H
authors.initials: CH
authors.lastname: Dean
authors.forename: Leigh-Anne D
authors.initials: LA
authors.lastname: Miller
authors.forename: April N
authors.initials: AN
authors.lastname: Smith
authors.forename: Daniel
authors.initials: D
authors.lastname: Dufort
authors.forename: Richard A
authors.initials: RA
authors.lastname: Lang
authors.forename: Lee A
authors.initials: LA
authors.lastname: Niswander
mesh_terms: D022005:Adherens Junctions / Q000502:physiology; D000818:Animals; D001483:Base Sequence; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation; D016373:DNA, Antisense / Q000235:genetics; D018076:DNA, Complementary / Q000235:genetics; D051526:Fibroblast Growth Factor 10 / Q000235:genetics / Q000502:physiology; D018507:Gene Expression Regulation, Developmental; D007765:Lacrimal Apparatus / Q000196:embryology*; D008168:Lung / Q000196:embryology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D009024:Morphogenesis; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology; D015854:Up-Regulation; D051153:Wnt Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051176:beta Catenin / Q000172:deficiency / Q000235:genetics / Q000502:physiology
chemical_list: D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D016373:DNA, Antisense; D018076:DNA, Complementary; C496464:Fgf10 protein, mouse; D051526:Fibroblast Growth Factor 10; D016212:Transforming Growth Factor beta; D051153:Wnt Proteins; D051176:beta Catenin