Grant: Operating Grant

The development of a normal placenta is essential for fetal growth and survival, and defects in its development are associated with common problems affecting the course of human pregnancy. The abnormal differentiation of the trophoblast cells that are involved in the implantation of the embryo and in the establishment of the maternal blood flow is linked to preeclampsia and, if severe, may affect fetal growth resulting in intrauterine growth restriction. By producing and analyzing Map2k1 and Map2k1 Map2k2 compound mouse mutants, we have established the essential and unique role played by MAP2K1 and MAP2K2 during placenta formation. Both MAP2K proteins are required for the normal response of the cell to specific signals during the formation of the placenta. However, they do not seem to be involved in the same processes. MAP2K1 is essential for the normal growth of the labyrinthine region of the placenta whereas MAP2K2 seems to be required for the differentiation of the syncytiotrophoblasts in absence of one Map2k1 allele. Both type of mutations are characterized by the underdevelopment and hypovascularization of the labyrinthine region leading to a non-functional placenta and the death of their progenies. The molecular mechanisms responsible for the specific functions of MAP2K1 and MAP2K2 are poorly understood. This application is aimed at elucidating the unique role(s) of Map2k1 and Map2k2 genes in signal transduction during embryonic and extra-embryonic development, as well as identifying the mechanisms involved in the specificity of signal transduction.