Aberrant neuronal differentiation and inhibition of dendrite outgrowth resulting from endoplasmic reticulum stress.
Aberrant neuronal differentiation and inhibition of dendrite outgrowth resulting from endoplasmic reticulum stress.
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DOI：
10.1002/jnr.23389
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发表时间：
2014-09
影响因子：
4.2
通讯作者：
Okuma, Yasunobu
中科院分区：
文献类型：
--
作者：
Kawada, Koichi;Iekumo, Takaaki;Saito, Ryo;Kaneko, Masayuki;Mimori, Seisuke;Nomura, Yasuyuki;Okuma, Yasunobu
神经干细胞(NSCs)在中枢神经系统的发育中起着重要作用。内质网应激可诱导神经元死亡。神经元死亡后，通常会加强神经再生以修复受损区域。然而，目前尚不清楚内质网应激是否直接影响神经发生相关的过程，如神经元分化和树突生长。我们评估了神经元分化和树突生长是否受到Hrd1的调节，Hrd1是一种泛素连接酶，在衣霉素诱导的内质网应激的温和条件下诱导。用维甲酸诱导小鼠胚胎肿瘤P19细胞分化为神经元。分化的细胞在有或没有衣霉素和Hrd1基因敲除的情况下培养8d。内质网应激源导致内质网应激水平显著增加。内质网应激可增加8d分化细胞神经元标志物βⅢ-微管蛋白的表达水平。然而，树突标记微管相关蛋白-2(MAP-2)阳性细胞的突起似乎在内质网应激下收缩。此外，内质网应激显著降低树突长度和MAP-2的表达水平，但不影响存活成熟神经元的数量。相反，Hrd1基因敲除后，βⅢ-微管蛋白和MAP-2等蛋白表达的变化消失。这些结果表明，内质网应激引起神经干细胞分化异常，继而抑制了突起的生长。这些事件可能是通过增加Hrd1的表达来调节的。
Neural stem cells (NSCs) play an essential role in development of the central nervous system. Endoplasmic reticulum (ER) stress induces neuronal death. After neuronal death, neurogenesis is generally enhanced to repair the damaged regions. However, it is unclear whether ER stress directly affects neurogenesis-related processes such as neuronal differentiation and dendrite outgrowth. We evaluated whether neuronal differentiation and dendrite outgrowth were regulated by HRD1, a ubiquitin ligase that was induced under mild conditions of tunicamycin-induced ER stress. Neurons were differentiated from mouse embryonic carcinoma P19 cells by using retinoic acid. The differentiated cells were cultured for 8 days with or without tunicamycin and HRD1 knockdown. The ER stressor led to markedly increased levels of ER stress. ER stress increased the expression levels of neuronal marker βIII-tubulin in 8-day-differentiated cells. However, the neurites of dendrite marker microtubule-associated protein-2 (MAP-2)-positive cells appeared to retract in response to ER stress. Moreover, ER stress markedly reduced the dendrite length and MAP-2 expression levels, whereas it did not affect the number of surviving mature neurons. In contrast, HRD1 knockdown abolished the changes in expression of proteins such as βIII-tubulin and MAP-2. These results suggested that ER stress caused aberrant neuronal differentiation from NSCs followed by the inhibition of neurite outgrowth. These events may be mediated by increased HRD1 expression.
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影响因子：
64.8
作者：
Apelqvist, Å;Li, H;Edlund, H
通讯作者：
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作者：
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