Interregulation between fragile X mental retardation protein and methyl CpG binding protein 2 in the mouse posterior cerebral cortex.
Interregulation between fragile X mental retardation protein and methyl CpG binding protein 2 in the mouse posterior cerebral cortex.
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脆性X智力低下蛋白与甲基CpG结合蛋白2在小鼠大脑后皮层的相互调节
DOI：
10.1093/hmg/ddaa226
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发表时间：
2021-02-04
影响因子：
3.5
通讯作者：
Hampson DR
中科院分区：
文献类型：
--
作者：
Arsenault J;Hooper AWM;Gholizadeh S;Kong T;Pacey LK;Koxhioni E;Niibori Y;Eubanks JH;Wang LY;Hampson DR
几种X连锁神经发育障碍，包括由MECP 2基因突变引起的Rett综合征和由FMR 1基因突变引起的脆性X综合征（FXS），都具有自闭症相关特征。编码甲基CpG结合蛋白2（MeCP 2）的mRNA先前已被鉴定为mRNA结合蛋白脆性X智力低下蛋白（FMRP）的底物，该蛋白在FXS中沉默。在这里，我们报告了FXS（Fmr 1敲除（KO））和Rett综合征（MeCP 2 KO）小鼠模型中基因表达的这两个关键调节因子之间的稳态关系。我们发现，在Fmr 1基因敲除小鼠大脑皮层中MeCP 2蛋白水平升高，而MeCP 2基因敲除小鼠显示FMRP水平降低，这暗示了MeCP 2和FMRP活性之间的相互作用。事实上，用短发夹RNA敲低MeCP 2导致小鼠Neuro 2A和人HEK-293细胞中FMRP的减少，表明这两种调节蛋白的表达水平相互偶联。脑室内注射编码FMRP的腺相关病毒载体导致MeCP 2在体内表达的同时减少，并部分纠正了运动过度活跃。此外，后皮质中MeCP 2的水平与Fmr 1 KO小鼠中多动表型的严重程度相关。这些结果表明MeCP 2和FMRP在先前未定义的稳态关系内操作。我们的研究结果还表明，MeCP 2在Fmr 1基因敲除小鼠大脑后皮质的过度表达可能有助于脆性X运动多动表型。 MeCP 2和FMRP之间的相互调节。MeCP 2是一种转录调节因子，有助于FMRP表达的上调。FMRP是一种翻译调节剂，有助于MeCP 2翻译的下调。MeCP 2 KO小鼠活动减退。Fmr 1 KO小鼠表现出活动过度。
Several X-linked neurodevelopmental disorders including Rett syndrome, induced by mutations in the MECP2 gene, and fragile X syndrome (FXS), caused by mutations in the FMR1 gene, share autism-related features. The mRNA coding for methyl CpG binding protein 2 (MeCP2) has previously been identified as a substrate for the mRNA-binding protein, fragile X mental retardation protein (FMRP), which is silenced in FXS. Here, we report a homeostatic relationship between these two key regulators of gene expression in mouse models of FXS (Fmr1 Knockout (KO)) and Rett syndrome (MeCP2 KO). We found that the level of MeCP2 protein in the cerebral cortex was elevated in Fmr1 KO mice, whereas MeCP2 KO mice displayed reduced levels of FMRP, implicating interplay between the activities of MeCP2 and FMRP. Indeed, knockdown of MeCP2 with short hairpin RNAs led to a reduction of FMRP in mouse Neuro2A and in human HEK-293 cells, suggesting a reciprocal coupling in the expression level of these two regulatory proteins. Intra-cerebroventricular injection of an adeno-associated viral vector coding for FMRP led to a concomitant reduction in MeCP2 expression in vivo and partially corrected locomotor hyperactivity. Additionally, the level of MeCP2 in the posterior cortex correlated with the severity of the hyperactive phenotype in Fmr1 KO mice. These results demonstrate that MeCP2 and FMRP operate within a previously undefined homeostatic relationship. Our findings also suggest that MeCP2 overexpression in Fmr1 KO mouse posterior cerebral cortex may contribute to the fragile X locomotor hyperactivity phenotype. Interregulation between MeCP2 and FMRP. MeCP2, a transcriptional modulator, contributes to the upregulation of FMRP expression. FMRP, a translational modulator, contributes to the downregulation of MeCP2 translation. MeCP2 KO mice are hypoactive. Fmr1 KO mice display hyperactivity.
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影响因子：
4.5
作者：
Li R;Dong Q;Yuan X;Zeng X;Gao Y;Chiao C;Li H;Zhao X;Keles S;Wang Z;Chang Q
通讯作者：
Chang Q
影响因子：
16.2
作者：
Edbauer, Dieter;Neilson, Joel R.;Foster, Kelly A.;Wang, Chi-Fong;Seeburg, Daniel P.;Batterton, Matthew N.;Tada, Tomoko;Dolan, Bridget M.;Sharp, Phillip A.;Sheng, Morgan
通讯作者：
Sheng, Morgan
影响因子：
2.9
作者：
Gholizadeh, Shervin;Halder, Sebok Kuvnar;Hampson, David R.
通讯作者：
Hampson, David R.
影响因子：
--
作者：
Gholizadeh, Shervin;Tharmalingam, Sujeenthar;Hampson, David R.
通讯作者：
Hampson, David R.
影响因子：
7.6
作者：
Gholizadeh, Shervin;Arsenault, Jason;Hampson, David R.
通讯作者：
Hampson, David R.