Embryonic death of Mek1-deficient mice reveals a role for this kinase in angiogenesis in the labyrinthine region of the placenta

Mek is a dual-specificity kinase that activates the extracellular-signal-re gulated (Erk) mitogen-activated protein (MAP) kinases upon agonist binding to receptors. The Erk MAP kinase cascade is involved in cell-fate determina tion in many organisms. In mammals, this pathway is proposed to regulate ce ll growth and differentiation. Genetic studies have shown that although a s ingle mek gene is present in Caenorhabditis elegans, Drosophila and Xenopus , two mek homologs, Mek1 and Mek2, are present in the mammalian cascade. In the present study, we describe a mutant mouse line in which the mek1 gene has been disrupted by insertional mutagenesis. The null mutation was recess ive lethal, as the homozygous mutant embryos died at 10.5 days of gestation . Histopathological analyses revealed a reduction in vascularization of the placenta that was due to a marked decrease of vascular endothelial cells i n the labyrinthine region. The failure to establish a functional placenta p robably explains the death of the mek1(-/-) embryos. Cell-migration assays indicated that mek1(-/-) fibroblasts could not be induced to migrate by fib ronectin, although the levels of Mek2 protein and Erk activation were norma l. Re-expression of Mek1 in the mutant mouse embryonic fibroblasts (MEFs) r estored their ability to migrate. Our findings provide genetic evidence tha t establishes the unique role played by Mek1 in signal transduction, They a lso suggest that mek1 function is required for normal response to angiogeni c signals that might promote vascularization of the labyrinthine region of the placenta.