Molecular Mechanisms Regulating the Defects in Fragile X Syndrome Neurons Derived from Human Pluripotent Stem Cells
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 re...
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| Format: | Article |
| Language: | English |
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Elsevier
2015-01-01
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| Series: | Stem Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213671114003373 |
| _version_ | 1811314767614181376 |
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| author | Tomer Halevy Christian Czech Nissim Benvenisty |
| author_facet | Tomer Halevy Christian Czech Nissim Benvenisty |
| author_sort | Tomer Halevy |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-13T11:18:19Z |
| format | Article |
| id | doaj.art-fd1cbea436fa472782f48146ed913827 |
| institution | Directory Open Access Journal |
| issn | 2213-6711 |
| language | English |
| last_indexed | 2024-04-13T11:18:19Z |
| publishDate | 2015-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Stem Cell Reports |
| spelling | doaj.art-fd1cbea436fa472782f48146ed9138272022-12-22T02:48:55ZengElsevierStem Cell Reports2213-67112015-01-01413746Molecular Mechanisms Regulating the Defects in Fragile X Syndrome Neurons Derived from Human Pluripotent Stem CellsTomer Halevy0Christian Czech1Nissim Benvenisty2Azrieli Center for Stem Cells and Genetic Research, Department of Genetics, Institute of Life Sciences, The Hebrew University, Givat-Ram, Jerusalem 91904, IsraelRoche Pharmaceutical Research & Early Development, Neuroscience, Roche Innovation Center, Grenzacherstrasse 124, 4070 Basel, SwitzerlandAzrieli Center for Stem Cells and Genetic Research, Department of Genetics, Institute of Life Sciences, The Hebrew University, Givat-Ram, Jerusalem 91904, Israel; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2213671114003373 |
| spellingShingle | Tomer Halevy Christian Czech Nissim Benvenisty Molecular Mechanisms Regulating the Defects in Fragile X Syndrome Neurons Derived from Human Pluripotent Stem Cells Stem Cell Reports |
| title | Molecular Mechanisms Regulating the Defects in Fragile X Syndrome Neurons Derived from Human Pluripotent Stem Cells |
| title_full | Molecular Mechanisms Regulating the Defects in Fragile X Syndrome Neurons Derived from Human Pluripotent Stem Cells |
| title_fullStr | Molecular Mechanisms Regulating the Defects in Fragile X Syndrome Neurons Derived from Human Pluripotent Stem Cells |
| title_full_unstemmed | Molecular Mechanisms Regulating the Defects in Fragile X Syndrome Neurons Derived from Human Pluripotent Stem Cells |
| title_short | Molecular Mechanisms Regulating the Defects in Fragile X Syndrome Neurons Derived from Human Pluripotent Stem Cells |
| title_sort | molecular mechanisms regulating the defects in fragile x syndrome neurons derived from human pluripotent stem cells |
| url | http://www.sciencedirect.com/science/article/pii/S2213671114003373 |
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