Critical role for DP5/Harakiri, a Bcl-2 homology domain 3-only Bcl-2 family member, in axotomy-induced neuronal cell death
Critical role for DP5/Harakiri, a Bcl-2 homology domain 3-only Bcl-2 family member, in axotomy-induced neuronal cell death
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DOI：
10.1523/jneurosci.5101-03.2004
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发表时间：
2004-04-14
影响因子：
5.3
通讯作者：
Nuñez, G
中科院分区：
文献类型：
--
作者：
Imaizumi, K;Benito, A;Nuñez, G
神经元的存活主要由抑制凋亡程序的神经营养因子维持。轴突切断术或外周靶点的去除会导致神经元细胞死亡，但对诱导这种类型的细胞死亡的机制仍知之甚少。在这里，我们表明，DP 5/Harakiri，Bcl-2家族的Bcl-2同源结构域3-唯一的成员，诱导运动神经元横断后的舌下神经在小鼠和交感神经元神经生长因子（NGF）撤出后。为了评估DP 5在神经元细胞死亡中的作用，通过基因靶向产生DP 5缺陷的突变小鼠。DP 5（-/-）小鼠存活，并表现出正常的出生后发育。值得注意的是，与来自DP 5（+/+）同窝小鼠的运动神经元相比，来自DP 5（-/-）小鼠的运动神经元被高度保护免于由切除舌下神经诱导的细胞死亡。此外，在上级颈神经节（SCG）神经元中DP 5的缺乏导致由NGF撤除触发的迟发性神经元细胞死亡。对DP 5（-/-）小鼠SCG神经元的分析显示，与野生型小鼠的神经元相比，线粒体膜电位的保留增加，caspase-3的活化减少。这些结果表明，DP 5通过调节线粒体功能和caspase-3活化在轴突切断和NGF剥夺诱导的神经元细胞死亡中起重要作用。
The survival of neurons is maintained primarily by neurotrophic factors that suppress the apoptotic program. Axotomy or removal of peripheral targets causes neuronal cell death, but the mechanisms involved in the induction of this type of cell death remain poorly understood. Here, we show that DP5/Harakiri, a Bcl-2 homology domain 3-only member of the Bcl-2 family, is induced in motoneurons after transection of the hypoglossal nerve in mice and in sympathetic neurons after nerve growth factor (NGF) withdrawal. To assess the role of DP5 in neuronal cell death, mutant mice deficient in DP5 were generated by gene targeting. DP5(-/-) mice were viable and exhibited normal postnatal development. Notably, motoneurons from DP5(-/-) mice were highly protected from cell death induced by resection of the hypoglossal nerve compared with motoneurons from DP5(+/+) littermate mice. In addition, deficiency of DP5 in superior cervical ganglia (SCG) neurons resulted in delayed neuronal cell death triggered by NGF withdrawal. Analysis of SCG neurons from DP5(-/-) mice revealed increased preservation of mitochondrial membrane potential and reduced activation of caspase-3 compared with neurons from wild-type mice. These results indicate that DP5 plays an important role in neuronal cell death induced by axotomy and NGF deprivation through the regulation of mitochondrial function and caspase-3 activation.