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

• Published in: Protein & cell 2021-08, Vol.12 (8), p.639-652
• Main Authors: Chen, Xiaoying, Han, Xu, Blanchi, Bruno, Guan, Wuqiang, Ge, Weihong, Yu, Yong-Chun, Sun, Yi E.
• Format: Article
• Language: English
• Subjects: Action Potentials - genetics; Base Sequence; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Differentiation; Developmental Biology; Dosage; Embryo cells; Fibroblasts - cytology; Fibroblasts - metabolism; Forebrain; Gene Dosage; Gene Expression; Gene Knockdown Techniques; Genetic Complementation Test; Human Embryonic Stem Cells - cytology; Human Embryonic Stem Cells - metabolism; Human Genetics; human pluripotent stem cell; Humans; Induced Pluripotent Stem Cells - cytology; Induced Pluripotent Stem Cells - metabolism; Inhibitory postsynaptic potentials; Life Sciences; MeCP2; MeCP2 protein; Methyl-CpG binding protein; Methyl-CpG-Binding Protein 2 - deficiency; Methyl-CpG-Binding Protein 2 - genetics; neural differentiation; Neural Stem Cells - metabolism; Neural Stem Cells - pathology; Neurodevelopmental disorders; Neurons; Neurons - metabolism; Neurons - pathology; Phenotype; Phenotypes; Primary Cell Culture; Prosencephalon - metabolism; Prosencephalon - pathology; Protein Science; Research Article; Rett Syndrome; Rett Syndrome - genetics; Rett Syndrome - metabolism; Rett Syndrome - pathology; Severity of Illness Index; Stem Cells; Synaptic Transmission
• ISSN: 1674-800X; 1674-8018
• DOI: 10.1007/s13238-020-00773-z

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.