Isoform-specific toxicity of Mecp2 in postmitotic neurons: suppression of neurotoxicity by FoxG1.
Isoform-specific toxicity of Mecp2 in postmitotic neurons: suppression of neurotoxicity by FoxG1.
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DOI：
10.1523/jneurosci.5841-11.2012
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发表时间：
2012-02-22
期刊：
影响因子：
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通讯作者：
D'Mello SR
中科院分区：
文献类型：
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作者：
Dastidar SG;Bardai FH;Ma C;Price V;Rawat V;Verma P;Narayanan V;D'Mello SR
甲基-CpG结合蛋白2（MeCP 2）是一种广泛表达的蛋白质，其突变引起Rett综合征。MeCP 2的水平在大脑中最高，在那里它选择性地在成熟神经元中表达。其在有丝分裂后神经元中的功能尚不清楚。MeCP 2基因被选择性剪接以产生具有不同N末端的两种蛋白质，命名为MeCP 2-e1和MeCP 2-e2。这两种亚型的生理学意义尚未阐明，通常认为它们在功能上是等同的。我们报道了在培养的小脑颗粒神经元中低钾处理诱导死亡和Aβ处理的皮质神经元中，Mecp 2-e2表达上调，而Mecp 2-e1亚型表达下调。Mecp 2-e2的敲低保护神经元免于死亡，而e1亚型的敲低则没有影响。强制表达MeCP 2-e2，而不是MeCP 2-e1，促进细胞凋亡，否则健康的神经元。我们发现MeCP 2-e2与叉头蛋白FoxG 1相互作用，其突变也会导致Rett综合征。FoxG 1已被证明促进神经元存活，其下调导致神经元死亡。我们发现FoxG 1表达升高抑制MeCP 2-e2神经毒性。MeCP 2-e2神经毒性也被IGF-1和Akt抑制，IGF-1可防止FoxG 1表达的神经元死亡相关下调，Akt的激活是FoxG 1介导的神经保护所必需的。最后，如果FoxG 1表达被抑制或在FoxG 1单倍缺陷小鼠培养的神经元中，MeCP 2-e2神经毒性增强。我们的研究结果表明，Mecp 2-E2促进神经元死亡，这种活动通常被FoxG 1抑制。FoxG 1表达减少释放Mecp 2-e2促进神经元死亡。
The methyl-CpG Binding Protein 2 (MeCP2) is a widely expressed protein, mutations of which cause Rett syndrome. The level of MeCP2 is highest in the brain where it is expressed selectively in mature neurons. Its functions in postmitotic neurons are not known. The MeCP2 gene is alternatively-spliced to generate two proteins with different N-termini, designated as MeCP2-e1 and MeCP2-e2. The physiological significance of these two isoforms has not been elucidated and it is generally assumed they are functionally equivalent. We report that in cultured cerebellar granule neurons induced to die by low potassium treatment and in Aβ-treated cortical neurons, Mecp2-e2 expression is upregulated whereas expression of the Mecp2-e1 isoform is downregulated. Knockdown of Mecp2-e2 protects neurons from death whereas knockdown of the e1 isoform has no effect. Forced expression of MeCP2-e2, but not MeCP2-e1, promotes apoptosis in otherwise healthy neurons. We find that MeCP2-e2 interacts with the forkhead protein FoxG1, mutations of which also cause Rett syndrome. FoxG1 has been shown to promote neuronal survival and its downregulation leads to neuronal death. We find that elevated FoxG1 expression inhibits MeCP2-e2 neurotoxicity. MeCP2-e2 neurotoxicity is also inhibited by IGF-1, which prevents the neuronal death-associated downregulation of FoxG1 expression, and by Akt, activation of which is necessary for FoxG1-mediated neuroprotection. Finally, MeCP2-e2 neurotoxicity is enhanced if FoxG1 expression is suppressed or in neurons cultured from FoxG1-haplodeficient mice. Our results indicate that Mecp2-e2 promotes neuronal death and that this activity is normally inhibited by FoxG1. Reduced FoxG1expression frees Mecp2-e2 to promote neuronal death.