OVEREXPRESSION OF BCL-2 IN TRANSGENIC MICE PROTECTS NEURONS FROM NATURALLY-OCCURRING CELL-DEATH AND EXPERIMENTAL-ISCHEMIA
OVEREXPRESSION OF BCL-2 IN TRANSGENIC MICE PROTECTS NEURONS FROM NATURALLY-OCCURRING CELL-DEATH AND EXPERIMENTAL-ISCHEMIA
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DOI：
10.1016/0896-6273(94)90266-6
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发表时间：
1994-10-01
期刊：
影响因子：
16.2
通讯作者：
HUARTE, J
中科院分区：
文献类型：
--
作者：
MARTINOU, JC;DUBOISDAUPHIN, M;HUARTE, J
自然发生的细胞死亡（NOCD）是神经系统发育的一个重要特征。在这个过程中，神经元表达bcl-2，一种细胞死亡的主要调节因子，其表达可能决定神经元的死亡或存活。为了深入了解bcl-2在体内NOCD过程中可能的作用，我们产生了转基因小鼠系，其中神经元在神经元特异性烯醇化酶（NSE）或磷酸甘油酸激酶（PCK）启动子的控制下过表达人BCL-2蛋白。BCL-2过表达减少了NOCD期间的神经元损失，这导致神经系统肥大。例如，视网膜的面神经核和神经节细胞层分别比正常人多40%和50%的神经元。与这一发现相一致的是，在面神经和视神经中发现了比正常更多的轴突。我们还测试了过度表达BCL-2的神经元是否对大脑中动脉闭塞引起的永久性缺血更具抵抗力;在转基因小鼠中，与野生型小鼠相比，脑梗死体积减少了50%。这些动物是研究神经元数量增加对大脑功能的影响以及控制神经元在发育和成年期间存活的机制的宝贵工具。
Naturally occurring cell death (NOCD) is a prominent feature of the developing nervous system. During this process, neurons express bcl-2, a major regulator of cell death whose expression may determine whether a neuron dies or survives. To gain insight into the possible role of bcl-2 during NOCD in vivo, we generated lines of transgenic mice in which neurons overexpress the human BCL-2 protein under the control of the neuron-specific enolase (NSE) or phosphoglycerate kinase (PCK) promoters. BCL-2 overexpression reduced neuronal loss during the NOCD period, which led to hypertrophy of the nervous system. For instance, the facial nucleus and the ganglion cell layer of the retina had, respectively, 40% and 50% more neurons than normal. Consistent with this finding, more axons than normal were found in the facial and optic nerves. We also tested whether neurons overexpressing BCL-2 were more resistant to permanent ischemia induced by middle cerebral artery occlusion; in transgenic mice, the volume of the brain infarction was reduced by 50% as compared with wildtype mice. These animals represent an invaluable tool for studying the effects of increased neuronal numbers on brain function as well as the mechanisms that control the survival of neurons during development and adulthood.