Wide spectrum of neuronal and network phenotypes in human stem cell-derived excitatory neurons with Rett syndrome-associated MECP2 mutations.
Wide spectrum of neuronal and network phenotypes in human stem cell-derived excitatory neurons with Rett syndrome-associated MECP2 mutations.
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DOI：
10.1038/s41398-022-02216-1
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发表时间：
2022-10-18
影响因子：
6.8
通讯作者：
Ellis, James
中科院分区：
文献类型：
--
作者：
Mok, Rebecca S. F.;Zhang, Wenbo;Sheikh, Taimoor, I;Pradeepan, Kartik;Fernandes, Isabella R.;DeJong, Leah C.;Benigno, Gabriel;Hildebrandt, Matthew R.;Mufteev, Marat;Rodrigues, Deivid C.;Wei, Wei;Piekna, Alina;Liu, Jiajie;Muotri, Alysson R.;Vincent, John B.;Muller, Lyle;Martinez-Trujillo, Julio;Salter, Michael W.;Ellis, James
瑞特综合征（RTT）是一种严重的神经发育障碍，主要由X连锁基因MECP2的杂合性功能丧失突变引起，MECP2是一种全局转录调节因子。MECP2的甲基-CpG结合结构域（MBD）突变会破坏其与甲基化DNA的相互作用。在此，我们研究了一名具有保留语言能力的非典型RTT患者的MBD中一种新型MECP2 L124W错义突变相对于严重的MECP2无效突变的影响。由于结合动力学降低，L124W蛋白破坏异染色质中心体的能力有限。我们分离出两对同基因的野生型（WT）和L124W诱导多能干细胞。L124W诱导的兴奋性神经元表达稳定的蛋白质，表现出输入电阻增加以及电压门控钠电流和钾电流降低，并且其神经元形态异常仅限于树突复杂性降低。三对同基因的MECP2无效神经元具有预期的更极端的形态和电生理表型。我们使用微电极阵列检测了L124W和MECP2无效兴奋性神经网络活动的发育和成熟情况。相对于同基因对照，L124W神经元的同步网络爆发频率增加，而MECP2无效神经元的同步网络爆发频率显著降低且网络爆发持续时间短暂延长。一个基于生物学原理的计算神经网络模型表明，观察到的网络动力学变化可由单个神经元内在的钠电流和钾电流变化来解释。我们的多层次研究结果表明，RTT兴奋性神经元呈现出广泛的形态、电生理和电路表型，这些表型取决于MECP2突变的严重程度。
Rett syndrome (RTT) is a severe neurodevelopmental disorder primarily caused by heterozygous loss-of-function mutations in the X-linked gene MECP2 that is a global transcriptional regulator. Mutations in the methyl-CpG binding domain (MBD) of MECP2 disrupt its interaction with methylated DNA. Here, we investigate the effect of a novel MECP2 L124W missense mutation in the MBD of an atypical RTT patient with preserved speech in comparison to severe MECP2 null mutations. L124W protein had a limited ability to disrupt heterochromatic chromocenters due to decreased binding dynamics. We isolated two pairs of isogenic WT and L124W induced pluripotent stem cells. L124W induced excitatory neurons expressed stable protein, exhibited increased input resistance and decreased voltage-gated Na+ and K+ currents, and their neuronal dysmorphology was limited to decreased dendritic complexity. Three isogenic pairs of MECP2 null neurons had the expected more extreme morphological and electrophysiological phenotypes. We examined development and maturation of L124W and MECP2 null excitatory neural network activity using micro-electrode arrays. Relative to isogenic controls, L124W neurons had an increase in synchronous network burst frequency, in contrast to MECP2 null neurons that suffered a significant decrease in synchronous network burst frequency and a transient extension of network burst duration. A biologically motivated computational neural network model shows the observed changes in network dynamics are explained by changes in intrinsic Na+ and K+ currents in individual neurons. Our multilevel results demonstrate that RTT excitatory neurons show a wide spectrum of morphological, electrophysiological and circuitry phenotypes that are dependent on the severity of the MECP2 mutation.
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影响因子：
5.9
作者：
Deneault E;White SH;Rodrigues DC;Ross PJ;Faheem M;Zaslavsky K;Wang Z;Alexandrova R;Pellecchia G;Wei W;Piekna A;Kaur G;Howe JL;Kwan V;Thiruvahindrapuram B;Walker S;Lionel AC;Pasceri P;Merico D;Yuen RKC;Singh KK;Ellis J;Scherer SW
通讯作者：
Scherer SW
影响因子：
21.1
作者：
Chen X;Han X;Blanchi B;Guan W;Ge W;Yu YC;Sun YE
通讯作者：
Sun YE
影响因子：
25
作者：
Ballas, Nurit;Lioy, Daniel T.;Grunseich, Christopher;Mandel, Gail
通讯作者：
Mandel, Gail
影响因子：
4.8
作者：
Georgel, PT;Horowitz-Scherer, RA;Hansen, JC
通讯作者：
Hansen, JC
影响因子：
3.3
作者：
Beltrao-Braga, Patricia C. B.;Pignatari, Graciela C.;Kerkis, Irina
通讯作者：
Kerkis, Irina