Abstract
Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the gene encoding the methyl-CpG-binding protein 2 (MeCP2). Among many different roles, MeCP2 has a high phenotypic impact during the different stages of brain development. Thus, it is essential to intensively investigate the function of MeCP2, and its regulated targets, to better understand the mechanisms of the disease and inspire the development of possible therapeutic strategies. Several animal models have greatly contributed to these studies, but more recently human pluripotent stem cells (hPSCs) have been providing a promising alternative for the study of RTT. The rapid evolution in the field of hPSC culture allowed first the development of 2D-based neuronal differentiation protocols, and more recently the generation of 3D human brain organoid models, a more complex approach that better recapitulates human neurodevelopment in vitro. Modeling RTT using these culture platforms, either with patient-specific human induced pluripotent stem cells (hiPSCs) or genetically-modified hPSCs, has certainly contributed to a better understanding of the onset of RTT and the disease phenotype, ultimately allowing the development of high throughput drugs screening tests for potential clinical translation. In this review, we first provide a brief summary of the main neurological features of RTT and the impact of MeCP2 mutations in the neuropathophysiology of this disease. Then, we provide a thorough revision of the more recent advances and future prospects of RTT modeling with human neural cells derived from hPSCs, obtained using both 2D and organoids culture systems, and its contribution for the current and future clinical trials for RTT.
Highlights
Rett syndrome (RTT) is a neurodevelopmental disorder with higher incidence in females, causing, in the majority of cases, mental retardation
Around 90% of the patients are diagnosed with a point mutation or small deletions in the methyl-CpG binding protein 2 (MeCP2) gene (
Upon differentiation into forebrain neurons, these cells exhibited phenotypic alterations including a reduced neuronal growth, a reduced dendritic complexity, and increased fragmentation and reduced mitochondrial membrane potential [77]. These observations were correlated with reduced CREB levels, a transcription factor known to indirectly regulate MeCP2 levels, and from which overexpression rescues the phenotype associated with RTT mutant neurons
Summary
Rett syndrome (RTT) is a neurodevelopmental disorder with higher incidence in females, causing, in the majority of cases, mental retardation. Considerable progress in understanding the mechanisms of RTT has been made in recent years by conducting studies in animal models, the male homozygous mice (MeCP2_/y) model being the most frequently used due to the early development of severe phenotype and the inexistence of a mosaic pattern [13]. The motivation to use alternative models, which more accurately resemble the severity and the features of RTT, has been growing In this context, human in vitro cellular models, both cultured in the format of 2D monolayer or as 3D aggregates, have been developed by using human-induced pluripotent stem cells (hiPSCs) reprogrammed from RTT patient somatic cells as the initial cell source. MeCP2 induces transcriptional modifications by altering chromatin conformation and by promoting the formation of the chromatin loop
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
