title: Crucial requirement of ERK/MAPK signaling in respiratory tract development.
abstract: The mammalian genome contains two ERK/MAP kinase genes, Mek1 and Mek2, which encode dual-specificity kinases responsible for ERK/MAP kinase activation. In order to define the function of the ERK/MAPK pathway in the lung development in mice, we performed tissue-specific deletions of Mek1 function on a Mek2 null background. Inactivation of both Mek genes in mesenchyme resulted in several phenotypes, including giant omphalocele, kyphosis, pulmonary hypoplasia, defective tracheal cartilage and death at birth. The absence of tracheal cartilage rings establishes the crucial role of intracellular signaling molecules in tracheal chondrogenesis and provides a putative mouse model for tracheomalacia. In vitro, the loss of Mek function in lung mesenchyme did not interfere with lung growth and branching, suggesting that both the reduced intrathoracic space due to the dysmorphic rib cage and the omphalocele impaired lung development in vivo. Conversely, Mek mutation in the respiratory epithelium caused lung agenesis, a phenotype resulting from the direct impact of the ERK/MAPK pathway on cell proliferation and survival. No tracheal epithelial cell differentiation occurred and no SOX2-positive progenitor cells were detected in mutants, implying a role for the ERK/MAPK pathway in trachea progenitor cell maintenance and differentiation. Moreover, these anomalies were phenocopied when the Erk1 and Erk2 genes were mutated in airway epithelium. Thus, the ERK/MAPK pathway is required for the integration of mesenchymal and epithelial signals essential for the development of the entire respiratory tract.
authors.affiliation: Centre de recherche sur le cancer de l'Université Laval, Centre Hospitalier Universitaire de Québec, L'Hôtel-Dieu de Québec, Québec, Canada G1R 2J6.
authors.forename: Olivier
authors.initials: O
authors.lastname: Boucherat
authors.affiliation: Centre de recherche sur le cancer de l'Université Laval, Centre Hospitalier Universitaire de Québec, L'Hôtel-Dieu de Québec, Québec, Canada G1R 2J6.
authors.forename: Valérie
authors.initials: V
authors.lastname: Nadeau
authors.affiliation: Centre de recherche sur le cancer de l'Université Laval, Centre Hospitalier Universitaire de Québec, L'Hôtel-Dieu de Québec, Québec, Canada G1R 2J6.
authors.forename: Félix-Antoine
authors.initials: FA
authors.lastname: Bérubé-Simard
authors.affiliation: Centre de recherche sur le cancer de l'Université Laval, Centre Hospitalier Universitaire de Québec, L'Hôtel-Dieu de Québec, Québec, Canada G1R 2J6 Department of Molecular Biology, Medical Biochemistry and Pathology, Université Laval, Québec, Canada G1V 0A6 jean.charron@crhdq.ulaval.ca lucie.jeannotte@crhdq.ulaval.ca.
authors.forename: Jean
authors.initials: J
authors.lastname: Charron
authors.affiliation: Centre de recherche sur le cancer de l'Université Laval, Centre Hospitalier Universitaire de Québec, L'Hôtel-Dieu de Québec, Québec, Canada G1R 2J6 Department of Molecular Biology, Medical Biochemistry and Pathology, Université Laval, Québec, Canada G1V 0A6 jean.charron@crhdq.ulaval.ca lucie.jeannotte@crhdq.ulaval.ca.
authors.forename: Lucie
authors.initials: L
authors.lastname: Jeannotte
mesh_terms: D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D002356:Cartilage / Q000196:embryology; D002454:Cell Differentiation; D049109:Cell Proliferation; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D008168:Lung / Q000196:embryology; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000502:physiology*; D048370:MAP Kinase Kinase 2 / Q000235:genetics / Q000502:physiology*; D020935:MAP Kinase Signaling System; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D012137:Respiratory System / Q000196:embryology*; D013234:Stem Cells / Q000166:cytology; D014132:Trachea / Q000196:embryology
chemical_list: D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482127:Map2k1 protein, mouse; C482129:Map2k2 protein, mouse
keywords: ERK/MAPK pathway; Lung agenesis; Lung morphogenesis; Mek gene function; Omphalocele; Trachea