Molecular mechanisms regulating the defects in fragile x syndrome neurons derived from human pluripotent stem cells

Tomer Halevy, Christian Czech, Nissim Benvenisty*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

71 Scopus citations


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.

Original languageAmerican English
Pages (from-to)37-46
Number of pages10
JournalStem Cell Reports
Issue number1
StatePublished - 13 Jan 2015

Bibliographical note

Funding Information:
We thank members of the Stem Cell Unit at the Hebrew University and especially Uri Weissbein and Tamar Golan-Lev for their assistance with graphical design of the figures and Dr. Ofra Yanuka for her technical assistance and many advises. N.B. is the Herbert Cohn Chair in Cancer Research. This work was partially supported by a Hoffmann La Roche-Yissum Collaboration grant and the Israel Science Foundation-Morasha Foundation (grant number 1252/12).

Publisher Copyright:
© 2015 The Authors.


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