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Activation of MAP3K DLK and LZK in Purkinje cells causes rapid and slow degeneration depending on signaling strength
eLife ( IF 6.4 ) Pub Date : 2021-01-21 , DOI: 10.7554/elife.63509
Yunbo Li 1 , Erin M Ritchie 1 , Christopher L Steinke 1 , Cai Qi 1 , Lizhen Chen 1 , Binhai Zheng 2, 3 , Yishi Jin 1, 2, 4
Affiliation  

The conserved MAP3K Dual leucine zipper kinases can activate JNK via MKK4 or MKK7. Vertebrate DLK and LZK share similar biochemical activities and undergo auto-activation upon increased expression. Depending on cell-type and nature of insults DLK and LZK can induce pro-regenerative, pro-apoptotic or pro-degenerative responses, although the mechanistic basis of their action is not well understood. Here, we investigated these two MAP3Ks in cerebellar Purkinje cells using loss- and gain-of function mouse models. While loss of each or both kinases does not cause discernible defects in Purkinje cells, activating DLK causes rapid death and activating LZK leads to slow degeneration. Each kinase induces JNK activation and caspase-mediated apoptosis independent of each other. Significantly, deleting CELF2, which regulates alternative splicing of Map2k7, strongly attenuates Purkinje cell degeneration induced by LZK, but not DLK. Thus, controlling the activity levels of DLK and LZK is critical for neuronal survival and health.

中文翻译:

浦肯野细胞中 MAP3K DLK 和 LZK 的激活导致快速和缓慢的退化,具体取决于信号强度

保守的 MAP3K 双亮氨酸拉链激酶可以通过 MKK4 或 MKK7 激活 JNK。脊椎动物 DLK 和 LZK 具有相似的生化活性,并在表达增加时进行自动激活。根据细胞类型和损伤的性质,DLK 和 LZK 可以诱导促再生、促凋亡或促退行性反应,尽管它们作用的机制基础尚不清楚。在这里,我们使用功能丧失和功能获得小鼠模型研究了小脑浦肯野细胞中的这两种 MAP3K。虽然每种或两种激酶的丢失不会导致浦肯野细胞出现明显缺陷,但激活 DLK 会导致快速死亡,而激活 LZK 会导致缓慢退化。每种激酶相互独立地诱导 JNK 激活和半胱天冬酶介导的细胞凋亡。重要的是,删除 CELF2,它调节 Map2k7 的可变剪接,强烈减弱由 LZK 而不是 DLK 诱导的浦肯野细胞变性。因此,控制 DLK 和 LZK 的活性水平对于神经元的存活和健康至关重要。
更新日期:2021-01-21
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