title: Essential role of the ERK/MAPK pathway in blood-placental barrier formation.
abstract: The mammalian genome contains two ERK/MAP kinase kinase genes, Map2k1 and Map2k2, which encode dual-specificity kinases responsible for ERK activation. Loss of Map2k1 function in mouse causes embryonic lethality due to placental defects, whereas Map2k2 mutants have a normal lifespan. The majority of Map2k1(+/-) Map2k2(+/-) embryos die during gestation from the underdevelopment of the placenta labyrinth, demonstrating that both kinases are involved in placenta formation. Map2k1(+/-) Map2k2(+/-) mutants show reduced vascularization of the labyrinth and defective formation of syncytiotrophoblast layer II (SynT-II) leading to the accumulation of multinucleated trophoblast giant cells (MTGs). To define the cell type-specific contribution of the ERK/MAPK pathway to placenta development, we performed deletions of Map2k1 function in different Map2k1 Map2k2 allelic backgrounds. Loss of MAP kinase kinase activity in pericytes or in allantois-derived tissues worsens the MTG phenotype. These results define the contribution of the ERK/MAPK pathway in specific embryonic and extraembryonic cell populations for normal placentation. Our data also indicate that MTGs could result from the aberrant fusion of SynT-I and -II. Using mouse genetics, we demonstrate that the normal development of SynT-I into a thin layer of multinucleated cells depends on the presence of SynT-II. Lastly, the combined mutations of Map2k1 and Map2k2 alter the expression of several genes involved in cell fate specification, cell fusion and cell polarity. Thus, appropriate ERK/MAPK signaling in defined cell types is required for the proper growth, differentiation and morphogenesis of the placenta.
authors.affiliation: Centre de recherche sur le cancer de l'Université Laval, Centre Hospitalier Universitaire de Québec, L'Hôtel-Dieu de Québec, 9 rue McMahon, Québec, QC, 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, 9 rue McMahon, Québec, QC, Canada G1R 2J6 jean.charron@crhdq.ulaval.ca.
authors.forename: Jean
authors.initials: J
authors.lastname: Charron
mesh_terms: D000482:Allantois / Q000201:enzymology; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D002459:Cell Fusion; D004268:DNA-Binding Proteins; D015536:Down-Regulation; D005260:Female; D017353:Gene Deletion; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D015726:Giant Cells / Q000166:cytology; D019426:Integrases / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008954:Models, Biological; D009479:Neuropeptides / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D010641:Phenotype; D010920:Placenta / Q000098:blood supply* / Q000166:cytology / Q000201:enzymology*; D011247:Pregnancy; D021381:Protein Transport; D011995:Recombination, Genetic / Q000235:genetics; D014157:Transcription Factors; D014327:Trophoblasts / Q000166:cytology / Q000201:enzymology
chemical_list: D015415:Biomarkers; D004268:DNA-Binding Proteins; C101631:Gcm1 protein, mouse; D009479:Neuropeptides; D047495:PPAR gamma; D014157:Transcription Factors; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482127:Map2k1 protein, mouse; C482129:Map2k2 protein, mouse; C045073:Cre recombinase; D019426:Integrases
keywords: MAP2K1 (MEK1); MAP2K2 (MEK2); Placenta morphogenesis; Syncytiotrophoblast differentiation