title: Map2k1 and Map2k2 genes contribute to the normal development of syncytiotrophoblasts during placentation.
abstract: The mammalian genome contains two ERK/MAP kinase kinase genes, Map2k1 and Map2k2, which encode dual-specificity kinases responsible for ERK/MAP kinase activation. In the mouse, loss of Map2k1 function causes embryonic lethality, whereas Map2k2 mutants survive with a normal lifespan, suggesting that Map2k1 masks the phenotype due to the Map2k2 mutation. To uncover the specific function of MAP2K2 and the threshold requirement of MAP2K proteins during embryo formation, we have successively ablated the Map2k gene functions. We report here that Map2k2 haploinsufficiency affects the normal development of placenta in the absence of one Map2k1 allele. Most Map2k1(+/-)Map2k2(+/-) embryos die during gestation because of placenta defects restricted to extra-embryonic tissues. The impaired viability of Map2k1(+/-)Map2k2(+/-) embryos can be rescued when the Map2k1 deletion is restricted to the embryonic tissues. The severity of the placenta phenotype is dependent on the number of Map2k mutant alleles, the deletion of the Map2k1 allele being more deleterious. Moreover, the deletion of one or both Map2k2 alleles in the context of one null Map2k1 allele leads to the formation of multinucleated trophoblast giant (MTG) cells. Genetic experiments indicate that these structures are derived from Gcm1-expressing syncytiotrophoblasts (SynT), which are affected in their ability to form the uniform SynT layer II lining the maternal sinuses. Thus, even though Map2k1 plays a predominant role, these results enlighten the function of Map2k2 in placenta development.
authors.affiliation: Centre de recherche en cancérologie de l'Université Laval, Centre Hospitalier Universitaire de Québec, L'Hôtel-Dieu de Québec, Québec, QC, G1R 2J6, Canada.
authors.forename: Valérie
authors.initials: V
authors.lastname: Nadeau
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Guillemette
authors.forename: Louis-François
authors.initials: LF
authors.lastname: Bélanger
authors.forename: Olivier
authors.initials: O
authors.lastname: Jacob
authors.forename: Sophie
authors.initials: S
authors.lastname: Roy
authors.forename: Jean
authors.initials: J
authors.lastname: Charron
mesh_terms: D000483:Alleles; D000818:Animals; D004789:Enzyme Activation; D005260:Female; D018507:Gene Expression Regulation, Developmental; D048369:MAP Kinase Kinase 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D048370:MAP Kinase Kinase 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D010920:Placenta / Q000196:embryology / Q000378:metabolism; D010929:Placentation / Q000235:genetics; D011247:Pregnancy; D014327:Trophoblasts / Q000378:metabolism*
chemical_list: D020928:Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482127:Map2k1 protein, mouse; C482129:Map2k2 protein, mouse