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

神经系统发育过程中细胞凋亡调控机制分析

• 批准号: 12480227
• 负责人: YOSHIDA Hiroki
• 金额: $ 8.64万
• 依托单位: KYUSHU UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12480227/
• 关键词: Apaf1; neuron; apoptosis; mitochondria; Apafl; Bcl-xL

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.

研究人员报告说，APAF1是一种适用于凋亡的线粒体途径的衔接子分子，在胚胎的大脑中强烈表达，并且APAF1缺陷型胚胎由于无法死亡的神经元的积累而显示出脑畸形。相反，研究人员已证明缺乏BCL-XL的小鼠是细胞凋亡的线粒体途径的调节分子，其凋亡神经元过多。该项目的目的是通过产生缺乏APAF1和BCL-XL（双KO小鼠）的小鼠来分析大脑发育过程中凋亡的调节机制。双KO胚胎显示出与Apaf1- single突变体胚胎相似的大脑畸形。它们还显示出凋亡神经元的丧失，APAF1单个突变体胚胎也是如此。因此，BCL-XL缺乏无法恢复APAF1缺乏效率的表型。有趣的是，双KO胚胎同时死亡（胚胎发生约13.5天），如Bcl-XL单链突变体胚胎。在双KO小鼠中观察到胎儿肝脏中造血细胞的大量凋亡，如Bcl-Xl-single突变体胚胎中。有人提出，APAF1和BCL-XL在胚胎发生过程中调节神经元的凋亡。

项目成果

Fujita, E. 他: "Detection of caspase-9 activation in the cell death of the Bcl-x-deficient mouse embryo nervous system by cleavage sites-directed antisera"Brain Res Dev Brain Res.. 122. 135-147 (2000)

Fujita, E. 等人：“通过切割位点定向抗血清检测 Bcl-x 缺陷型小鼠胚胎神经系统细胞死亡中的 caspase-9 激活”Brain Res Dev Brain Res.. 122. 135-147 ( 2000)

Guo Z他: "Inactivation of the retinoblastoma tumor suppressor induces apoptosis protease-activating factor-1 dependent and independent apoptotic pathways during embryogenesis"Cancer Res. 61・23. 8395-8400 (2001)

郭Z等人：“视网膜母细胞瘤肿瘤抑制因子的失活在胚胎发生过程中诱导凋亡蛋白酶激活因子1依赖性和非依赖性凋亡途径”Cancer Res. 61・23 (2001)。

Miyazaki K 他: "Caspase-independent cell death and mitochondrial disrupsions observed in the apaf1-deficient cells"J. Biochem (Tokyo). 129・6. 963-969 (2001)

Miyazaki K 等：“在 apaf1 缺陷细胞中观察到的不依赖于半胱天冬酶的细胞死亡和线粒体破坏”J. Biochem（东京）129·6（2001）。

Urase, K. 他: "Bcl-xL is a negative regulator of caspase-3 activation in immature neurons during development"Brain Res Dev Brain Res.. 116. 69-78 (1999)

Urase, K. 等人：“Bcl-xL 是发育过程中未成熟神经元中 caspase-3 激活的负调节因子” Brain Res Dev Brain Res.. 116. 69-78 (1999)

Guo, Z., et al.: "Inactivation of the Retinoblastoma Tumor Suppressor Induces Apoptosis Protease-activating Factor-1 Dependent and Independent Apoptotic Pathways during Embryogenesis"Cancer Res. 61. 8395-8400 (2001)

郭，Z.，等人：“胚胎发生过程中视网膜母细胞瘤肿瘤抑制因子的失活诱导凋亡蛋白酶激活因子 1 依赖和独立的凋亡途径”Cancer Res。