TY - JOUR
T1 - Neural differentiation of fragile X human embryonic stem cells reveals abnormal patterns of development despite successful neurogenesis
AU - Telias, Michael
AU - Segal, Menahem
AU - Ben-Yosef, Dalit
N1 - Funding Information:
This research was partly funded by a grant from the Chief Scientist Office of the Israel Ministry of Health ( 300000-6237 ), by a grant from the Israel Science Foundation ( 227/06 ) and by an Excellency Grant from Tel-Aviv Sourasky Medical Center .
PY - 2013/2/1
Y1 - 2013/2/1
N2 - 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.
AB - 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.
KW - Abnormal development
KW - Fragile X syndrome
KW - Human embryonic stem cells
KW - Intellectual disability
KW - Neural differentiation
UR - http://www.scopus.com/inward/record.url?scp=84872370488&partnerID=8YFLogxK
U2 - 10.1016/j.ydbio.2012.11.031
DO - 10.1016/j.ydbio.2012.11.031
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AN - SCOPUS:84872370488
SN - 0012-1606
VL - 374
SP - 32
EP - 45
JO - Developmental Biology
JF - Developmental Biology
IS - 1
ER -