Vascular abnormalities and deregulation of VEGF in Lkb1-deficient mice

The LKB1 tumor suppressor gene, mutated in Peutz-Jeghers syndrome, encodes a serine/threonine kinase of unknown function. Here we show that mice with a targeted disruption of Lkb1 die at midgestation, with the embryos showing neural tube defects, mesenchymal cell death, and vascular abnormalities. E xtraembryonic development was also severely affected; the mutant placentas exhibited defective labyrinth layer development and the fetal vessels faile d to invade the placenta. These phenotypes were associated,with tissue-spec ific deregulation of vascular endothelial growth factor (VEGF) expression, including a marked increase in the amount of VEGF messenger RNA. Moreover, VEGF production in cultured Lkb1(-/-) fibroblasts was elevated in both norm oxic and hypoxic conditions. These findings place Lkb1 in the VEGF signalin g pathway and suggest that the vascular defects accompanying Lkb1 loss are mediated at least in part by VEGF.