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. Extraembryonic development was also severely affected; the mutant placentas exhibited defective labyrinth layer development and the fetal vessels failed to invade the placenta. These phenotypes were associated with tissue-specific 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 normoxic and hypoxic conditions. These findings place Lkb1 in the VEGF signaling pathway and suggest that the vascular defects accompanying Lkb1 loss are mediated at least in part by VEGF.
Ylikorkala
A
A
Molecular and Cancer Biology Program, Haartman Institute and Biomedicum Helsinki, Post Office Box 63, University of Helsinki, Helsinki 00014, Finland.
Rossi
D J
DJ
Korsisaari
N
N
Luukko
K
K
Alitalo
K
K
Henkemeyer
M
M
Mäkelä
T P
TP
D055372:AMP-Activated Protein Kinases; D000818:Animals; D001808:Blood Vessels / Q000002:abnormalities* / Q000196:embryology; D016923:Cell Death; D015687:Cell Hypoxia; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism; D004622:Embryo, Mammalian / Q000378:metabolism*; D005314:Embryonic and Fetal Development; D016228:Endothelial Growth Factors / Q000235:genetics* / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000002:abnormalities / Q000166:cytology / Q000196:embryology; D018507:Gene Expression Regulation, Developmental; D018390:Gene Targeting; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D017403:In Situ Hybridization; D008222:Lymphokines / Q000235:genetics* / Q000378:metabolism*; D008648:Mesoderm / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000002:abnormalities / Q000166:cytology / Q000196:embryology; D009436:Neural Tube Defects / Q000196:embryology; D009687:Nuclear Proteins / Q000378:metabolism; D010641:Phenotype; D010920:Placenta / Q000098:blood supply / Q000196:embryology / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D004268:DNA-Binding Proteins; D016228:Endothelial Growth Factors; C497443:Hif1a protein, mouse; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008222:Lymphokines; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases