Post-natal lethality and neurological and gastrointestinal defects in mice with targeted disruption of the A-Raf protein kinase gene

The Ras/Raf/MEK/MAP kinase cascade transmits signals from activated cell-surface receptors to transcription factors in the nucleus and is an essential component of metazoan intracellular signaling pathways (see, for example, [1-6]), In the mouse, the Raf protein kinase family is comprised of three homologous genes, Raf-1, A-Raf and B-Raf [5] which are ubiquitously expressed in the developing embryo [7], We have introduced into the mouse germ line a loss-of-function mutation in the X-chromosomal A-Raf gene, by homologous recombination in embryonic stem cells, On a predominantly C57 B1/6 genetic background, A-Raf-deficient mice displayed neurological and intestinal abnormalities and died between 7 and 21 days postpartum, When the mutated allele was maintained on a predominantly 129/OLA background, by contrast, A-Raf-deficient animals survived to adulthood, did not display obvious intestinal abnormalities, were fertile, but did have a subset of the neurological defects.