Abstract
Fragile X syndrome (FXS) is a neurodevelopmental disorder, characterized by intellectual disability and sensory deficits, caused by epigenetic silencing of the FMR1 gene and subsequent loss of its protein product, fragile X mental retardation protein (FMRP). Delays in synaptic and neuronal development in the cortex have been reported in FXS mouse models; however, the main goal of translating lab research into pharmacological treatments in clinical trials has been so far largely unsuccessful, leaving FXS a still incurable disease. Here, we generated 2D and 3D in vitro human FXS model systems based on isogenic FMR1 knock-out mutant and wild-type human induced pluripotent stem cell (hiPSC) lines. Phenotypical and functional characterization of cortical neurons derived from FMRP-deficient hiPSCs display altered gene expression and impaired differentiation when compared with the healthy counterpart. FXS cortical cultures show an increased number of GFAP positive cells, likely astrocytes, increased spontaneous network activity, and depolarizing GABAergic transmission. Cortical brain organoid models show an increased number of glial cells, and bigger organoid size. Our findings demonstrate that FMRP is required to correctly support neuronal and glial cell proliferation, and to set the correct excitation/inhibition ratio in human brain development.
Highlights
Introduction FragileX syndrome (FXS), first described by J
We report the phenotypical and functional characterization of fragile X mental retardation protein (FMRP)-deficient hiPSCderived cortical neurons, which display altered gene expression and impaired differentiation when compared with the isogenic control
In order to produce an in vitro Fragile X syndrome (FXS) model system made of isogenic mutant and control human induced pluripotent stem cell (hiPSC) lines, we generated a FMRP knock-out line by gene editing in a FMRP wildtype genetic background
Summary
Introduction FragileX syndrome (FXS), first described by J. As a widely expressed RNA binding protein in the brain, FMRP plays a pivotal role in the stability and translational regulation of hundreds of mRNAs involved in synaptic protein synthesis[6], synaptic plasticity, and neuronal development[7,8,9]. Absence or incorrect expression of FMRP is directly linked with alterations in dendritic spine architecture, synaptogenesis, and neural connectivity, as suggested by profound alterations of anatomical development in the cortex of Fmr[1] knock-out (Fmr[1] KO) mice[5,10]. In vivo studies on Fmr[1] KO mice have revealed many aspects of FXS pathophysiology, providing fundamental information on the functionality of FMRP and its involvement in neurogenesis, neuronal maturation, and synaptic plasticity formation[11,12,13].
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