title: Neural differentiation of Fragile X human Embryonic Stem Cells reveals abnormal patterns of development despite successful neurogenesis.
abstract: Fragile X Syndrome (FXS) is the most common form of inherited intellectual disability, caused by developmentally regulated inactivation of FMR1, leading to the absence of its encoded protein FMRP. We have previously shown that undifferentiated Fragile X human Embryonic Stem Cells (FX-hESCs) express FMRP, despite the presence of the full FMR1 mutation (>200 CGG repeats). We describe here, for the first time, in-vitro differentiation of FX-hESCs into neurons progressively inactivating FMR1. Abnormal neurogenesis and aberrant gene expression were found already during early stages of differentiation, leading to poor neuronal maturation and high gliogenic development. Human FX neurons fired action potentials but displayed poor spontaneous synaptic activity and lacked reactivity to glutamate. Our dynamic FX-hESCs model can contribute to the understanding of the sequence of developmental events taking place during neurogenesis and how they are altered in FXS individuals, leading to intellectual disability. Furthermore, it may shed light over the striking phenotypic features characterizing FXS in human.
authors.affiliation: Stem Cell Research Lab, Racine IVF Unit, Lis Maternity Hospital, Tel-Aviv Sourasky Medical Center, 6 Weizmann St., 64239 Tel-Aviv, Israel.
authors.forename: Michael
authors.initials: M
authors.lastname: Telias
authors.forename: Menahem
authors.initials: M
authors.lastname: Segal
authors.forename: Dalit
authors.initials: D
authors.lastname: Ben-Yosef
mesh_terms: D002454:Cell Differentiation; D019070:Cell Lineage; D004594:Electrophysiology; D053595:Embryonic Stem Cells / Q000166:cytology*; D005434:Flow Cytometry; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D006801:Humans; D008954:Models, Biological; D009420:Nervous System; D055495:Neurogenesis; D009457:Neuroglia / Q000378:metabolism*; D009474:Neurons / Q000166:cytology* / Q000378:metabolism; D010641:Phenotype; D013997:Time Factors
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; C497683:FMR1 protein, human