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

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.