title: R-spondin 2 is required for normal laryngeal-tracheal, lung and limb morphogenesis.
abstract: Herein, we demonstrate that Lrp6-mediated R-spondin 2 signaling through the canonical Wnt pathway is required for normal morphogenesis of the respiratory tract and limbs. We show that the footless insertional mutation creates a severe hypomorphic R-spondin 2 allele (Rspo2(Tg)). The predicted protein encoded by Rspo2(Tg) neither bound the cell surface nor activated the canonical Wnt signaling reporter TOPFLASH. Rspo2 activation of TOPFLASH was dependent upon the second EGF-like repeat of Lrp6. Rspo2(Tg/Tg) mice had severe malformations of laryngeal-tracheal cartilages, limbs and palate, and lung hypoplasia consistent with sites of Rspo2 expression. Rspo2(Tg/Tg) lung defects were associated with reduced branching, a reduction in TOPGAL reporter activity, and reduced expression of the downstream Wnt target Irx3. Interbreeding the Rspo2(Tg) and Lrp6(-) alleles resulted in more severe defects consisting of marked lung hypoplasia and absence of tracheal-bronchial rings, laryngeal structures and all limb skeletal elements.
authors.affiliation: Section of Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children's Hospital Medical Center and The University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
authors.forename: Sheila M
authors.initials: SM
authors.lastname: Bell
authors.forename: Claire M
authors.initials: CM
authors.lastname: Schreiner
authors.forename: Susan E
authors.initials: SE
authors.lastname: Wert
authors.forename: Michael L
authors.initials: ML
authors.lastname: Mucenski
authors.forename: William J
authors.initials: WJ
authors.lastname: Scott
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Whitsett
mesh_terms: D000818:Animals; D001483:Base Sequence; D018076:DNA, Complementary / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D005121:Extremities / Q000196:embryology*; D005260:Female; D026502:LDL-Receptor Related Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D007830:Larynx / Q000002:abnormalities / Q000196:embryology*; D017880:Limb Deformities, Congenital / Q000209:etiology / Q000235:genetics; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D008168:Lung / Q000002:abnormalities / Q000196:embryology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009024:Morphogenesis; D016254:Mutagenesis, Insertional; D011247:Pregnancy; D015398:Signal Transduction; D019699:Thrombospondins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014132:Trachea / Q000002:abnormalities / Q000196:embryology*; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics; D051153:Wnt Proteins / Q000502:physiology; D000098907:R-Spondins
chemical_list: D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D026502:LDL-Receptor Related Proteins; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D019699:Thrombospondins; D014157:Transcription Factors; D051153:Wnt Proteins; C555476:Lrp6 protein, mouse; C518904:RSPO2 protein, mouse; D000098907:R-Spondins; C490035:Sp8 protein, mouse