Loss of the fragile X mental retardation protein causes aberrant differentiation in human neural progenitor cells

Abstract

Fragile X syndrome (FXS) is caused by transcriptional silencing of the FMR1 gene during embryonic development with the consequent loss of the encoded fragile X mental retardation protein (FMRP). The pathological mechanisms of FXS have been extensively studied using the Fmr1-knockout mouse, and the findings suggest important roles for FMRP in synaptic plasticity and proper functioning of neural networks. However, the function of FMRP during early development in the human nervous system remains to be confirmed. Here we describe human neural progenitor cells (NPCs) as a model for studying FMRP functions and FXS pathology. Transcriptome analysis of the NPCs derived from FMR1-knockout human induced pluripotent stem cells (iPSCs) showed altered expression of neural differentiation markers, particularly a marked induction of the astrocyte marker glial fibrillary acidic protein (GFAP). When induced to differentiate, FMRP-deficient neurons continued to express GFAP, and showed less spontaneous calcium bursts than the parental iPSC-derived neurons. Interestingly, the aberrant expression of GFAP and the impaired firing was corrected by treatment with the protein kinase inhibitor LX7101. These findings underscore the modulatory roles of FMRP in human neurogenesis, and further demonstrate that the defective phenotype of FXS could be reversed at least partly by small molecule kinase inhibitors.

Using Zebrafish to Model Autism Spectrum Disorder: A Comparison of ASD Risk Genes Between Zebrafish and Their Mammalian Counterparts

“…This expanded repeat is thought to result in hypermethylation of the X chromosome in males and active X chromosome in females (Bardoni et al, 2001). The protein product, FMRP, controls the production of other neuronal proteins at synapses by binding their coding region and repressing translation (Sunamura et al, 2018). Through this mechanism, FMRP is thought to interact with pre-and postsynaptic proteins important for synaptic plasticity (Sunamura et al, 2018).…”

“…The protein product, FMRP, controls the production of other neuronal proteins at synapses by binding their coding region and repressing translation (Sunamura et al, 2018). Through this mechanism, FMRP is thought to interact with pre-and postsynaptic proteins important for synaptic plasticity (Sunamura et al, 2018). While Fragile X syndrome itself is separate from autism, it is the leading monogenic cause of autism, as a significant proportion of individuals with FXS also meet the clinical diagnostic criteria for ASD (Feinstein and Reiss, 1998) and mutations in FMR1 are present in up to 5 percent of ASD cases (Reddy, 2005).…”

Altered cortical Cytoarchitecture in the Fmr1 knockout mouse

“…Earlier studies have documented the involvement of FMRP in embryonic neurogenesis, where embryonic Fmr1 KO mice displayed accelerated neurogenesis, increased neuronal differentiation and enhanced accumulation of progenitors in the subventricular zone [40][41][42]. These newly differentiated FMRP-deficient neurons exhibit abnormal functional properties such as altered calcium responses and bursts activity [40,43]. As a result, non-functional neurons that could not be integrated into the local circuitry are eliminated, which may explain the reduction in neuron number.…”

Inhibition of mTOR delayed but could not prevent experimental collapsing focal segmental glomerulosclerosis

“…Antibodies used to detect the pS6RP, the S6RP and the housekeeping gene γ-tubulin are shown in Table 1. These antibodies are well established and commonly used 18,19,21,[30][31][32][33] . The fluorescent signal was analysed with the Odyssey Imaging System (LI-COR Biosciences) and Odyssey Image studio Software (version 4.0).…”