Analyses of regulatory mechanisms of apoptosis during the development of nervous system

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The investigators have reported that Apaf1, an adaptor molecule that works for the mitochondrial pathways of apoptosis, is strongly expressed in the brain of embryos and also that Apaf1-deficient embryos showed brain deformities due to accumulation of neurons that failed to die by apoptosis. Contrary, mice that lack Bcl-xl, a regulatory molecule of the mitochondrial pathways of apoptosis, have been shown by the investigators to have excess of apoptotic neurons. The aim of the project is to analyze the regulatory mechanisms of apoptosis during the development of brains by generating mice that lack both Apaf1 and Bcl-xl (double KO mice).The double KO embryos showed similar brain deformities to Apaf1-single mutant embryos. They also showed loss of apoptotic neurons, as did Apaf1-single mutant embryos. Thus, Bcl-xl-deficiency could not restore the phenotypes of Apaf1-deficiency. Interestingly, the double KO embryos died at the same time (around 13.5 days of embryogenesis) as Bcl-xl-single mutant embryos. Massive apoptosis of hematopoietic cells in fetal liver was observed in the double KO mice, as in Bcl-xl-single mutant embryos. It has been suggested that Apaf1 and Bcl-xl differentially regulate the apoptosis of neurons during embryogenesis.