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

研究人员报道了Apaf1，一种用于线粒体凋亡途径的衔接分子，在胚胎的大脑中强烈表达，并且Apaf1缺失的胚胎由于神经元的积累而导致大脑畸形，而这些神经元未能因凋亡而死亡。相反，研究人员发现，缺乏Bcl-xl（一种线粒体凋亡途径的调节分子）的小鼠有过多的凋亡神经元。该项目的目的是通过培养同时缺乏Apaf1和Bcl-xl的小鼠（双KO小鼠）来分析脑发育过程中细胞凋亡的调控机制。双KO胚胎表现出与apaf1单突变胚胎相似的脑畸形。它们也显示了凋亡神经元的丢失，apaf1单突变胚胎也是如此。因此，缺乏bcl -xl不能恢复apaf1缺乏的表型。有趣的是，双KO胚胎与bcl -xl-单突变胚胎在同一时间（胚胎发生13.5天左右）死亡。与bcl -xl-单突变胚胎一样，双KO小鼠的胎儿肝脏中存在大量造血细胞凋亡。有研究表明，Apaf1和Bcl-xl在胚胎发生过程中对神经元凋亡的调控存在差异。

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.