{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T02:53:23Z","timestamp":1789872803929,"version":"4.0.1"},"reference-count":59,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2022,8,17]],"date-time":"2022-08-17T00:00:00Z","timestamp":1660694400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Biomorasha, Israel Science Foundation","award":["1471\/17"],"award-info":[{"award-number":["1471\/17"]}]},{"name":"The Sagol fund for embryos and stem cells as part of the Sagol Network","award":["1471\/17"],"award-info":[{"award-number":["1471\/17"]}]},{"name":"BrainBoost, Sagol School of Neuroscience","award":["1471\/17"],"award-info":[{"award-number":["1471\/17"]}]},{"name":"Leo Mintz, Tel Aviv University","award":["1471\/17"],"award-info":[{"award-number":["1471\/17"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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 TGF\u03b2\/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 TGF\u03b2\/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.<\/jats:p>","DOI":"10.3390\/ijms23169278","type":"journal-article","created":{"date-parts":[[2022,8,17]],"date-time":"2022-08-17T21:23:56Z","timestamp":1660771436000},"page":"9278","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Transcriptomic Analysis of Human Fragile X Syndrome Neurons Reveals Neurite Outgrowth Modulation by the TGF\u03b2\/BMP Pathway"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9705-6697","authenticated-orcid":false,"given":"Liron","family":"Kuznitsov-Yanovsky","sequence":"first","affiliation":[{"name":"Wolfe PGD Stem Cell Lab, Racine IVF Unit, Lis Maternity Hospital Tel-Aviv Sourasky Medical Center, Tel Aviv 64239, Israel"},{"name":"Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv 69978, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9376-4955","authenticated-orcid":false,"given":"Guy","family":"Shapira","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv 69978, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2735-5568","authenticated-orcid":false,"given":"Lital","family":"Gildin","sequence":"additional","affiliation":[{"name":"Wolfe PGD Stem Cell Lab, Racine IVF Unit, Lis Maternity Hospital Tel-Aviv Sourasky Medical Center, Tel Aviv 64239, Israel"},{"name":"Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv 69978, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9913-6124","authenticated-orcid":false,"given":"Noam","family":"Shomron","sequence":"additional","affiliation":[{"name":"Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv 69978, Israel"},{"name":"Sagol School of Neuroscience, Tel-Aviv University, Tel Aviv 69978, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dalit","family":"Ben-Yosef","sequence":"additional","affiliation":[{"name":"Wolfe PGD Stem Cell Lab, Racine IVF Unit, Lis Maternity Hospital Tel-Aviv Sourasky Medical Center, Tel Aviv 64239, Israel"},{"name":"Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv 69978, Israel"},{"name":"Sagol School of Neuroscience, Tel-Aviv University, Tel Aviv 69978, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1016\/0092-8674(91)90397-H","article-title":"Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome","volume":"65","author":"Verkerk","year":"1991","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1038\/s41583-021-00432-0","article-title":"The molecular biology of FMRP: New insights into fragile X syndrome","volume":"22","author":"Richter","year":"2021","journal-title":"Nat. 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