Implication of MEK1 and MEK2 in the establishment of the blood–placenta barrier during placentogenesis in mouse

Abstract

The ERK/MAPK signalling cascade is involved in many cellular functions. In mice, the targeted ablation of genes coding for members of this pathway is often associated with embryonic death due to the abnormal development of the placenta. The placenta is essential for nutritional and gaseous exchanges between maternal and embryonic circulations, as well as for the elimination of metabolic waste. These exchanges occur without direct contact between the two circulations. In mice, the blood–placenta barrier consists of a triple layer of trophoblast cells adjacent to endothelial cells from the embryo. In the ERK/MAPK cascade, MEK1 and MEK2 are dual-specificity kinases responsible for the activation of the ERK1 and ERK2 kinases. Inactivation of Mek1 causes placental malformations resulting from defective proliferation and differentiation of the labyrinthine trophoblast cells and leading to a severe delay in the development and the vascularization of the placenta, which explains the embryonic death. Although Mek2−/− mutants survive without any apparent phenotype, a large proportion of Mek1+/−Mek2+/− double heterozygous mutants die during gestation from placenta anomalies affecting the establishment of the blood–placenta barrier. Together, these data reveal how crucial is the role of the ERK/MAPK pathway during the formation of the placenta.In normal cells, various cellular processes are tightly controlled via a cascade of protein kinases, which transduce various signals from the cell surface to the nucleus to activate programmes of cell growth and differentiation. This network of sequential protein kinases referred to as the mitogen-activated protein kinase (MAPK) signalling cascade has been conserved during evolution. Our studies on the role of Mek1 and Mek2, components of this cascade, during mouse development have shown that both Mek1 and Mek2 genes contribute to normal morphogenesis and vascularization of the placenta. Mek1 mutant mice die during gestation of abnormal development of the labyrinthine region of the placenta. In contrast, Mek2 mutant mice are viable without any obvious anomaly. However, a majority of double heterozygous Mek1+/−Mek2+/− embryos die during late gestation from placental defects. Thus, the lack of one allele of each Mek gene is deleterious to embryo survival suggesting a potential contribution of Mek2 to placenta development. Despite similarities in their biochemical properties, MEK1 and MEK2 appear to have specific biological functions. Our long-term objective is to unravel the molecular mechanisms responsible for the specificity of action of MEK1 and MEK2 as well as to identify in which cellular processes the ERK/MAPK cascade is implicated. Characterization of the mechanisms involved in signal transduction is essential for our comprehension of the role of the ERK/MAPK signalling cascade in placenta diseases.