KIAA1199: A novel regulator of MEK/ERK-induced Schwann cell dedifferentiation
KIAA1199: A novel regulator of MEK/ERK-induced Schwann cell dedifferentiation
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DOI：
10.1002/glia.23188
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发表时间：
2017-10-01
期刊：
影响因子：
6.2
通讯作者：
Franzen, Rachelle
中科院分区：
文献类型：
--
作者：
Boerboom, Angelique;Reusch, Celine;Franzen, Rachelle
调节雪旺细胞（SC）可塑性的分子机制以及Nrg 1/ErbB诱导的MEK 1/ERK 1/2信号通路在SC去分化或髓鞘形成中的作用仍不清楚。目前认为，不同水平的MEK 1/ERK 1/2活化定义了SC分化的状态。因此，MEK 1/ERK 1/2信号转导的新调节剂的鉴定可能有助于破译驱动该通路对SC可塑性的影响的上下文特定方面。从这个角度来看，我们研究了KIAA 1199在SC可塑性中的潜在作用，KIAA 1199是一种促进癌细胞中ErbB和MEK 1/ERK 1/2信号传导的蛋白质。我们使用基于RNA干扰的策略在SC衍生的MSC 80细胞系中耗尽KIAA 1199，并且还使用Cre-lox技术产生了他莫昔芬诱导型和条件性小鼠模型，其中KIAA 1199通过同源重组失活。我们表明，SC中KIAA 1199的失效降低了cJun和其他髓鞘形成负调节因子的表达，并提高了Krox 20，将它们推向前髓鞘形成表型。我们进一步表明，在去分化条件下，对KIAA 1199无效的SC表现出较低的髓鞘清除率以及增加的髓鞘形成能力。最后，当KIAA 1199不存在时，Nrg 1诱导的MEK/ERK/1/2通路的活化严重减少，表明KIAA 1199促进SC中Nrg 1依赖性MEK 1和ERK 1/2活化。总之，这项工作确定KIAA 1199作为一种新的调节MEK/ERK诱导的SC去分化，并有助于更好地了解SC去分化的分子控制。
The molecular mechanisms that regulate Schwann cell (SC) plasticity and the role of the Nrg1/ErbB-induced MEK1/ERK1/2 signalling pathway in SC dedifferentiation or in myelination remain unclear. It is currently believed that different levels of MEK1/ERK1/2 activation define the state of SC differentiation. Thus, the identification of new regulators of MEK1/ERK1/2 signalling could help to decipher the context-specific aspects driving the effects of this pathway on SC plasticity. In this perspective, we have investigated the potential role of KIAA1199, a protein that promotes ErbB and MEK1/ERK1/2 signalling in cancer cells, in SC plasticity. We depleted KIAA1199 in the SC-derived MSC80 cell line with RNA-interference-based strategy and also generated Tamoxifen-inducible and conditional mouse models in which KIAA1199 is inactivated through homologous recombination, using the Cre-lox technology. We show that the invalidation of KIAA1199 in SC decreases the expression of cJun and other negative regulators of myelination and elevates Krox20, driving them towards a pro-myelinating phenotype. We further show that in dedifferentiation conditions, SC invalidated for KIAA1199 exhibit lower myelin clearance as well as increased myelination capacity. Finally, the Nrg1-induced activation of the MEK/ERK/1/2 pathway is severely reduced when KIAA1199 is absent, indicating that KIAA1199 promotes Nrg1-dependent MEK1 and ERK1/2 activation in SCs. In conclusion, this work identifies KIAA1199 as a novel regulator of MEK/ERK-induced SC dedifferentiation and contributes to a better understanding of the molecular control of SC dedifferentiation.