Mature neurons dynamically restrict apoptosis via redundant premitochondrial brakes.
Mature neurons dynamically restrict apoptosis via redundant premitochondrial brakes.
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DOI：
10.1111/febs.13944
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发表时间：
2016-12
期刊：
影响因子：
--
通讯作者：
Deshmukh M
中科院分区：
文献类型：
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作者：
Annis RP;Swahari V;Nakamura A;Xie AX;Hammond SM;Deshmukh M
凋亡细胞死亡对神经系统的早期发育至关重要，但一旦神经系统建立，凋亡通路在成熟神经元中受到高度限制。然而，在这些成熟神经元中增加对凋亡的抵抗的机制尚不完全清楚。我们之前发现，miR-29 microRNAs家族成员（miRNAs）可以诱导神经元成熟，并且miR-29的过表达足以限制神经元的凋亡。为了确定内源性miR-29是否单独对成熟神经元细胞色素c释放的抑制负责，我们检查了所有三个miR-29家族成员的交感神经元缺陷的凋亡通路的状态。出乎意料的是，我们发现在缺乏mir -29的成熟神经元中，凋亡途径在很大程度上仍然受到限制。因此，我们探索了成熟神经元抵抗凋亡的其他机制。我们发现miR-24是另一个在成熟小脑和交感神经元中上调的miRNA，它可以通过靶向类似的促死亡BH3-only基因与miR-29一起冗余作用。这些结果表明，成熟神经元参与冗余制动来限制凋亡途径并确保其长期存活。
Apoptotic cell death is critical for the early development of the nervous system, but once the nervous system is established, the apoptotic pathway becomes highly restricted in mature neurons. However, the mechanisms underlying this increased resistance to apoptosis in these mature neurons are not completely understood. We have previously found that members of the miR-29 family of microRNAs (miRNAs) are induced with neuronal maturation and that overexpression of miR-29 was sufficient to restrict apoptosis in neurons. To determine whether endogenous miR-29 alone was responsible for the inhibition of cytochrome c release in mature neurons, we examined the status of the apoptotic pathway in sympathetic neurons deficient for all three miR-29 family members. Unexpectedly, we found that the apoptotic pathway remained largely restricted in miR-29-deficient mature neurons. We therefore probed for additional mechanisms by which mature neurons resist apoptosis. We identify miR-24 as another miRNA that is upregulated in the maturing cerebellum and sympathetic neurons that can act redundantly with miR-29 by targeting a similar repertoire of pro-death BH3-only genes. These results reveal that mature neurons engage redundant brakes to restrict the apoptotic pathway and ensure their long-term survival.