Endothelial apoptosis in Braf-deficient mice.
Tyrosine kinase growth factor receptors and Ras/Raf/MEK/MAPK signalling have been implicated in the suppression as well as augmentation of programmed cell death. In addition, a Ras-independent role for Raf as a suppressor of programmed cell death has been suggested by the recent finding that Craf1 interacts with members of the Bcl-2 family at mitochondrial membranes. However, genetic studies of C. elegans and Drosophila, as well as the targeted mutagenesis of the murine Araf gene, have failed to support such a role. Here we show that mice with a targeted disruption in the Braf gene die of vascular defects during mid-gestation. Braf -/- embryos, unlike Araf -/- or Craf1 -/- embryos (L.W. et al., unpublished), show an increased number of endothelial precursor cells, dramatically enlarged blood vessels and apoptotic death of differentiated endothelial cells. These results establish Braf as a critical signalling factor in the formation of the vascular system and provide the first genetic evidence for an essential role of Raf gene in the regulation of programmed cell death.
Wojnowski
L
L
Section on Genetics, National Institute of Mental Health/National Human Genome Research Institute, Bethesda, Maryland 20892, USA.
Zimmer
A M
AM
Beck
T W
TW
Hahn
H
H
Bernal
R
R
Rapp
U R
UR
Zimmer
A
A
D000818:Animals; D017209:Apoptosis; D015152:Blotting, Northern; D015139:Blotting, Southern; D002454:Cell Differentiation; D004622:Embryo, Mammalian / Q000166:cytology; D004730:Endothelium, Vascular / Q000166:cytology* / Q000196:embryology; D018507:Gene Expression Regulation, Developmental; D018390:Gene Targeting; D005838:Genotype; D006579:Heterozygote; D006651:Histocytochemistry; D006720:Homozygote; D017403:In Situ Hybridization; D051379:Mice; D008822:Mice, Transgenic; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D019908:Proto-Oncogene Proteins c-raf; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology
D011518:Proto-Oncogene Proteins; D017346:Protein Serine-Threonine Kinases; D019908:Proto-Oncogene Proteins c-raf