Pre-clinical Investigation of Rett Syndrome Using Human Stem Cell-Based Disease Models.

Florencia D Haase,Bronte Coorey,Laurence C Cantrill,Patrick P L Tam,Lisa Riley,Wendy A Gold

doi:10.3389/fnins.2021.698812

Abstract

Rett syndrome (RTT) is an X-linked neurodevelopmental disorder, mostly caused by mutations in MECP2. The disorder mainly affects girls and it is associated with severe cognitive and physical disabilities. Modeling RTT in neural and glial cell cultures and brain organoids derived from patient- or mutation-specific human induced pluripotent stem cells (iPSCs) has advanced our understanding of the pathogenesis of RTT, such as disease-causing mechanisms, disease progression, and cellular and molecular pathology enabling the identification of actionable therapeutic targets. Brain organoid models that recapitulate much of the tissue architecture and the complexity of cell types in the developing brain, offer further unprecedented opportunity for elucidating human neural development, without resorting to conventional animal models and the limited resource of human neural tissues. This review focuses on the new knowledge of RTT that has been gleaned from the iPSC-based models as well as limitations of the models and strategies to refine organoid technology in the quest for clinically relevant disease models for RTT and the broader spectrum of neurodevelopmental disorders.

Highlights

Since the discovery that mutations in the methyl-CpG-binding protein 2 (MECP2) gene were the underlying cause of Rett syndrome (RTT), a great amount of work has been undertaken to understand the molecular function of MeCP2 (Amir et al, 1999; Figure 1)
MeCP2 was initially identified as a transcriptional repressor located in the nucleus that bound to methylated DNA (Lewis et al, 1992)
Modeling the Synaptic and Electrophysiological Phenotype of RTT Cells Rett syndrome is known to be a disorder of neuronal plasticity (Dani et al, 2005; Zhang et al, 2008; Maliszewska-Cyna et al, 2010) where aberrant expression of receptors and neurotransmitters suggest that MeCP2 is required to maintain synaptic excitation and inhibition that are fundamental to normal circuitry function (Blackman et al, 2012)

Summary

Introduction

Since the discovery that mutations in the MECP2 gene were the underlying cause of RTT, a great amount of work has been undertaken to understand the molecular function of MeCP2 (Amir et al, 1999; Figure 1). IPSCs from RTT patient fibroblasts have been successfully differentiated into neuronal progenitor cells (NPCs), neurons and glia and the modeling has recapitulated some of the cellular and physiological phenotypes of these cell types, including morphological and electrophysiological defects.

Results

Conclusion