Embryonic lethality and fetal liver apoptosis in mice lacking the c-raf-1 gene

The Raf kinases play a key role in relaying signals elicited by mitogens or oncogenes, Here, we report that c-raf-1(-/-) embryos are growth retarded and die at midgestation with anomalies in the placenta and in the fetal liver. Although hepatoblast proliferation does not appear to be impaired, c-raf-1(-/-) fetal livers are hypocellular and contain numerous apoptotic cells. Similarly, the poor proliferation of Raf-1(-/-) fibroblasts and hematopoietic cells cultivated in vitro is due to an increase in the apoptotic index of these cultures rather than to a cell cycle defect. Furthermore, Raf-1-deficient fibroblasts are more sensitive than wildtype cells to specific apoptotic stimuli, such as actinomycin D or Fas activation, but not to tumor necrosis factor-alpha. MEK/ERK activation is normal in Raf-l-deficient cells and embryos, and is probably mediated by B-Raf, These results indicate that the essential function of Raf-l is to counteract apoptosis rather than to promote proliferation, and that effecters distinct from the MEK/ERK cascade must mediate the anti-apoptotic function of Raf-1.