Neuronal maturation defect in induced pluripotent stem cells from patients with Rett syndrome

Abstract

Rett syndrome (RTT) is one of the most prevalent female neurodevelopmental disorders that cause severe mental retardation. Mutations in methyl CpG binding protein 2 (MeCP2) are mainly responsible for RTT. Patients with classical RTT exhibit normal development until age 6-18 mo, at which point they become symptomatic and display loss of language and motor skills, purposeful hand movements, and normal head growth. Murine genetic models and postmortem human brains have been used to study the disease and enable the molecular dissection of RTT. In this work, we applied a recently developed reprogramming approach to generate a novel in vitro human RTT model. Induced pluripotent stem cells (iPSCs) were derived from RTT fibroblasts by overexpressing the reprogramming factors OCT4, SOX2, KLF4, and MYC. Intriguingly, whereas some iPSCs maintained X chromosome inactivation, in others the X chromosome was reactivated. Thus, iPSCs were isolated that retained a single active X chromosome expressing either mutant or WT MeCP2, as well as iPSCs with reactivated X chromosomes expressing both mutant and WT MeCP2. When these cells underwent neuronal differentiation, the mutant monoallelic or biallelelic RTT-iPSCs displayed a defect in neuronal maturation consistent with RTT phenotypes. Our in vitro model of RTT is an important tool allowing the further investigation of the pathophysiology of RTT and the development of the curative therapeutics.

Modeling hepatitis C virus infection using human induced pluripotent stem cells

“…The discovery of cellular reprogramming and the ability to generate host-and tissue-specific cells from induced pluripotent stem cells (iPSCs) have the potential to transform the study of development, infectious disease, and degenerative disorders (1,2). For example, iPSCs have been used for the mechanistic study of a variety of cells types implicated in a wide diversity of disease (e.g., Friedreich ataxia, long-QT syndrome, Leopard syndrome, Rett syndrome, and α-1-antitrypsin disease) (3)(4)(5)(6)(7). However, no iPSC models of any infectious disease have been reported to date.…”

The Use of Induced Pluripotent Stem Cell Technology to Advance Autism Research and Treatment

“…A subsequent study using the RTT iPSC model also observed a reduced soma and nuclear size in affected neurons [102]. Kim et al [103] observed a neuronal maturation defect in iPSCs derived from RTT. In a recent report, Williams et al [104] generated astrocytes from RTT iPSCs and demonstrated that these mutant astrocytes and their conditioned media are enough to induce neuronal abnormalities.…”

Epileptic Encephalopathies: New Genes and New Pathways

“…Neurons from RTT-iPSCs have recapitulated phenotypes observed in both murine models and patients. In vitro phenotypes include reduced soma/nuclear size, lower expression of neuronal markers, and reduced dendrite spine density [140][141][142][143]. RTT-iPSC derived neurons also display a reduction in the transient rise of intracellular calcium levels typical of active synapses as well as a decrease in the frequency/amplitude of spontaneous excitatory and inhibitory postsynaptic currents [140].…”