title: Molecular mechanisms regulating the defects in fragile X syndrome neurons derived from human pluripotent stem cells.
abstract: 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.
authors.affiliation: Azrieli Center for Stem Cells and Genetic Research, Department of Genetics, Institute of Life Sciences, The Hebrew University, Givat-Ram, Jerusalem 91904, Israel.
authors.forename: Tomer
authors.initials: T
authors.lastname: Halevy
authors.affiliation: Roche Pharmaceutical Research & Early Development, Neuroscience, Roche Innovation Center, Grenzacherstrasse 124, 4070 Basel, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Czech
authors.affiliation: Azrieli Center for Stem Cells and Genetic Research, Department of Genetics, Institute of Life Sciences, The Hebrew University, Givat-Ram, Jerusalem 91904, Israel. Electronic address: nissimb@cc.huji.ac.il.
authors.forename: Nissim
authors.initials: N
authors.lastname: Benvenisty
mesh_terms: D001369:Axons / Q000378:metabolism; D001665:Binding Sites; D002454:Cell Differentiation / Q000235:genetics*; D016000:Cluster Analysis; D015536:Down-Regulation; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics* / Q000378:metabolism; D005600:Fragile X Syndrome / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics; D008954:Models, Biological; D055495:Neurogenesis / Q000235:genetics; D009474:Neurons / Q000166:cytology* / Q000378:metabolism*; D010641:Phenotype; D039904:Pluripotent Stem Cells / Q000166:cytology* / Q000378:metabolism*; D011485:Protein Binding; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000099229:RE1-Silencing Transcription Factor
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D035683:MicroRNAs; D012333:RNA, Messenger; D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor; C497683:FMR1 protein, human; C555413:MIRN382 microRNA, human