title: Molecular mechanisms regulating impaired neurogenesis of fragile X syndrome human embryonic stem cells.
abstract: Fragile X syndrome (FXS) is the most common form of inherited cognitive impairment. It is caused by developmental inactivation of the FMR1 gene and the absence of its encoded protein FMRP, which plays pivotal roles in brain development and function. In FXS embryos with full FMR1 mutation, FMRP is expressed during early embryogenesis and is gradually downregulated at the third trimester of pregnancy. FX-human embryonic stem cells (FX-hESCs), derived from FX human blastocysts, demonstrate the same pattern of developmentally regulated FMR1 inactivation when subjected to in vitro neural differentiation (IVND). In this study, we used this in vitro human platform to explore the molecular mechanisms downstream to FMRP in the context of early human embryonic neurogenesis. Our results show a novel role for the SOX superfamily of transcription factors, specifically for SOX2 and SOX9, which could explain the reduced and delayed neurogenesis observed in FX cells. In addition, we assess in this study the "GSK3β theory of FXS" for the first time in a human-based model. We found no evidence for a pathological increase in GSK3β protein levels upon cellular loss of FMRP, in contrast to what was found in the brain of Fmr1 knockout mice. Our study adds novel data on potential downstream targets of FMRP and highlights the importance of the FX-hESC IVND system.
authors.affiliation: 1 The Wolfe PGD-SC Lab, Racine IVF Unit, Lis Maternity Hospital, Tel Aviv Sourasky Medical Center , Tel Aviv, Israel .|2 Department of Cell and Developmental Biology Sackler Medical School, Tel Aviv University , Tel Aviv, Israel .
authors.forename: Michael
authors.initials: M
authors.lastname: Telias
authors.affiliation: 1 The Wolfe PGD-SC Lab, Racine IVF Unit, Lis Maternity Hospital, Tel Aviv Sourasky Medical Center , Tel Aviv, Israel .
authors.forename: Yoav
authors.initials: Y
authors.lastname: Mayshar
authors.affiliation: 1 The Wolfe PGD-SC Lab, Racine IVF Unit, Lis Maternity Hospital, Tel Aviv Sourasky Medical Center , Tel Aviv, Israel .
authors.forename: Ami
authors.initials: A
authors.lastname: Amit
authors.affiliation: 1 The Wolfe PGD-SC Lab, Racine IVF Unit, Lis Maternity Hospital, Tel Aviv Sourasky Medical Center , Tel Aviv, Israel .|2 Department of Cell and Developmental Biology Sackler Medical School, Tel Aviv University , Tel Aviv, Israel .
authors.forename: Dalit
authors.initials: D
authors.lastname: Ben-Yosef
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D002478:Cells, Cultured; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics*; D005600:Fragile X Syndrome / Q000235:genetics / Q000473:pathology*; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics; D000071679:Glycogen Synthase Kinase 3 beta; D000066449:Human Embryonic Stem Cells / Q000166:cytology*; D006801:Humans; D055495:Neurogenesis / Q000235:genetics*; D009474:Neurons / Q000378:metabolism
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; C497683:FMR1 protein, human; C497684:Fmr1 protein, mouse; C000605506:GSK3B protein, human; C000605507:Gsk3b protein, mouse