Volume 12 Issue 8
Aug.  2021
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Xiaoying Chen, Xu Han, Bruno Blanchi, Wuqiang Guan, Weihong Ge, Yong-Chun Yu, Yi E. Sun. Graded and pan-neural disease phenotypes of Rett Syndrome linked with dosage of functional MeCP2[J]. Protein&Cell, 2021, 12(8): 639-652. doi: 10.1007/s13238-020-00773-z
Citation: Xiaoying Chen, Xu Han, Bruno Blanchi, Wuqiang Guan, Weihong Ge, Yong-Chun Yu, Yi E. Sun. Graded and pan-neural disease phenotypes of Rett Syndrome linked with dosage of functional MeCP2[J]. Protein&Cell, 2021, 12(8): 639-652. doi: 10.1007/s13238-020-00773-z

Graded and pan-neural disease phenotypes of Rett Syndrome linked with dosage of functional MeCP2

doi: 10.1007/s13238-020-00773-z
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We thank the members of the Sun and Yu laboratory for helpful discussion and critical reading of the manuscript. We thank Xiaoqing Zhang and Songhai Shi for helpful comments on the project.
This study is supported by the National Key research and development program (2016YFA 0100801), the Natural Science Foundation of China (31930044, 31725012, 31620103904), the Foundation of Shanghai Municipal Education Commission (2019-01-07-00-07-E00062), the Collaborative Innovation Program of Shanghai Municipal Health Commission (2020CXJQ01), the Shanghai Municipal Science and Technology Major Project (No. 2018SHZDZX01) and ZJ Lab to Y.-C.Y.

  • Received Date: 2020-04-17
  • Rev Recd Date: 2020-07-06
  • Rett syndrome (RTT) is a progressive neurodevelopmental disorder, mainly caused by mutations in MeCP2 and currently with no cure. We report here that neurons from R106W MeCP2 RTT human iPSCs as well as human embryonic stem cells after MeCP2 knockdown exhibit consistent and long-lasting impairment in maturation as indicated by impaired action potentials and passive membrane properties as well as reduced soma size and spine density. Moreover, RTT-inherent defects in neuronal maturation could be pan-neuronal and occurred in neurons with both dorsal and ventral forebrain features. Knockdown of MeCP2 led to more severe neuronal deficits as compared to RTT iPSC-derived neurons, which appeared to retain partial function. Strikingly, consistent deficits in nuclear size, dendritic complexity and circuitry-dependent spontaneous postsynaptic currents could only be observed in MeCP2 knockdown neurons but not RTT iPSC-derived neurons. Both neuron-intrinsic and circuitry-dependent deficits of MeCP2- deficient neurons could be fully or partially rescued by re-expression of wild type or T158M MeCP2, strengthening the dosage dependency of MeCP2 on disease phenotypes and also the partial function of the mutant. Our findings thus reveal stable neuronal maturation deficits and unexpectedly, graded sensitivities of neuron-inherent and neural transmission phenotypes towards the extent of MeCP2 deficiency, which is informative for future therapeutic development.
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