Molecular Mechanisms Regulating the Defects in Fragile X Syndrome Neurons Derived from Human Pluripotent Stem Cells

Abstract

Summary: Fragile X syndrome (FXS) is caused by the absence of the fragile X mental retardation protein (FMRP). We have previously generated FXS-induced pluripotent stem cells (iPSCs) from patients’ fibroblasts. In this study, we aimed at unraveling the molecular phenotype of the disease. Our data revealed aberrant regulation of neural differentiation and axon guidance genes in FXS-derived neurons, which are regulated by the RE-1 silencing transcription factor (REST). Moreover, we found REST to be elevated in FXS-derived neurons. As FMRP is involved in the microRNA (miRNA) pathway, we employed miRNA-array analyses and uncovered several miRNAs dysregulated in FXS-derived neurons. We found hsa-mir-382 to be downregulated in FXS-derived neurons, and introduction of mimic-mir-382 into these neurons was sufficient to repress REST and upregulate its axon guidance target genes. Our data link FMRP and REST through the miRNA pathway and show a new aspect in the development of FXS. : In this article, Benvenisty and colleagues show that fragile X-derived neurons are aberrantly regulating neural differentiation and axon guidance genes due to elevated expression of the REST transcription repressor. They further suggest that the high levels of REST result from low levels of hsa-mir-382. Introduction of mimic-mir-382 into fragile X-derived neurons repressed REST and upregulated its axon guidance target genes.