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Embryonic lethality and fetal liver apoptosis in mice lacking the c-raf-1 gene
M Mikula1, M Schreiber, Z Husak
1Department of Cell- and Microbiology, Institute of Microbiology and Genetics and Research Institute of Molecular Pathology, Vienna Biocenter, 1030 Vienna, Austria.
Abstract:
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 wild- type 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-1-deficient cells and embryos, and is probably mediated by B-RAF. These results indicate that the essential function of Raf-1 is to counteract apoptosis rather than to promote proliferation, and that effectors distinct from the MEK/ERK cascade must mediate the anti-apoptotic function of Raf-1.
Insights
The study found that c-raf-1 (Raf-1) is essential for preventing apoptosis, not promoting proliferation. Raf-1 deficiency leads to increased cell death and developmental defects, with anti-apoptotic functions distinct from the MEK/ERK pathway.
Area of Science:
- Cell Biology
- Molecular Biology
- Developmental Biology
Background:
- Raf kinases are crucial signaling molecules involved in cellular responses to mitogens and oncogenes.
- The specific role of c-raf-1 (Raf-1) in embryonic development and cell survival remains incompletely understood.
Purpose of the Study:
- To investigate the essential function of Raf-1 in embryonic development and cellular homeostasis.
- To determine whether Raf-1's primary role is in cell proliferation or apoptosis regulation.
- To identify the signaling pathways mediating Raf-1's anti-apoptotic effects.
Main Methods:
- Generation and analysis of c-raf-1 knockout (c-raf-1(-/-)) mouse embryos.
- Assessment of cell proliferation and apoptosis in fetal tissues (liver) and cultured cells (fibroblasts, hematopoietic cells).
- Evaluation of sensitivity to apoptotic stimuli (actinomycin D, Fas activation, TNF-alpha) and MEK/ERK pathway activation.
Main Results:
- c-raf-1(-/-) embryos exhibit growth retardation, midgestation lethality, and placental/fetal liver anomalies.
- Raf-1 deficient fetal livers are hypocellular due to increased apoptosis, not impaired hepatoblast proliferation.
- Raf-1 deficient fibroblasts and hematopoietic cells show increased apoptosis in vitro and heightened sensitivity to specific apoptotic triggers.
- MEK/ERK activation is normal in Raf-1 deficient cells and embryos, suggesting mediation by B-RAF.
Conclusions:
- Raf-1's essential function is to counteract apoptosis, rather than to promote proliferation.
- The anti-apoptotic role of Raf-1 is mediated by effectors distinct from the canonical MEK/ERK cascade.
- These findings highlight a critical role for Raf-1 in maintaining cellular and organismal survival.
