Transcriptomic Analysis of Human Fragile X Syndrome Neurons Reveals Neurite Outgrowth Modulation by the TGFβ/BMP Pathway

Liron Kuznitsov-Yanovsky, Guy Shapira, Lital Gildin, Noam Shomron, Dalit Ben-Yosef*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Fragile X Syndrome (FXS) is the main genetic reason for intellectual disability and is caused by the silencing of fragile X mental retardation protein (FMRP), an RNA-binding protein regulating the translation of many neuronal mRNAs. Neural differentiation of FX human embryonic stem cells (hESC) mimics the neurodevelopment of FXS fetuses and thus serves as a good model to explore the mechanisms underlining the development of FXS. Isogenic hESC clones with and without the FX mutation that share the same genetic background were in vitro differentiated into neurons, and their transcriptome was analyzed by RNA sequencing. FX neurons inactivating FMR1 expression presented delayed neuronal development and maturation, concomitant with dysregulation of the TGFβ/BMP signaling pathway, and genes related to the extracellular matrix. Migration assay showed decreased neurite outgrowth in FX neurons that was rescued by inhibition of the TGFβ/BMP signaling pathway. Our results provide new insights into the molecular pathway by which loss of FMRP affects neuronal network development. In FX neurons, the lack of FMRP dysregulates members of the BMP signaling pathway associated with ECM organization which, in a yet unknown mechanism, reduces the guidance of axonal growth cones, probably leading to the aberrant neuronal network function seen in FXS.

Original languageEnglish
Article number9278
JournalInternational Journal of Molecular Sciences
Issue number16
StatePublished - Aug 2022


FundersFunder number
Biomorasha, Israel Science Foundation1471/17
Tel Aviv University
Sagol School of Neuroscience, Tel Aviv University


    • Fragile X syndrome
    • RNA sequencing
    • TGFβ/BMP pathway
    • human embryonic stem cells
    • neural differentiation
    • neurite outgrowth


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