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Graded and pan-neural disease phenotypes of Rett Syndrome linked with dosage of functional MeCP2.
- Source :
-
Protein & cell [Protein Cell] 2021 Aug; Vol. 12 (8), pp. 639-652. Date of Electronic Publication: 2020 Aug 27. - Publication Year :
- 2021
-
Abstract
- 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.<br /> (© 2020. The Author(s).)
- Subjects :
- Action Potentials genetics
Base Sequence
Cell Differentiation
Fibroblasts cytology
Fibroblasts metabolism
Gene Dosage
Gene Expression
Gene Knockdown Techniques
Genetic Complementation Test
Human Embryonic Stem Cells cytology
Human Embryonic Stem Cells metabolism
Humans
Induced Pluripotent Stem Cells cytology
Induced Pluripotent Stem Cells metabolism
Methyl-CpG-Binding Protein 2 deficiency
Neural Stem Cells pathology
Neurons pathology
Phenotype
Primary Cell Culture
Prosencephalon pathology
Rett Syndrome metabolism
Rett Syndrome pathology
Severity of Illness Index
Synaptic Transmission
Methyl-CpG-Binding Protein 2 genetics
Neural Stem Cells metabolism
Neurons metabolism
Prosencephalon metabolism
Rett Syndrome genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1674-8018
- Volume :
- 12
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Protein & cell
- Publication Type :
- Academic Journal
- Accession number :
- 32851591
- Full Text :
- https://doi.org/10.1007/s13238-020-00773-z