Regulatory Discrimination of mRNAs by FMRP Controls Adult Neural Stem Cell Differentiation

Fragile X syndrome (FXS) is caused by the loss of fragile X mental retardation protein (FMRP), a translation-inhibitor RNA binding protein. The impact of FMRP-deficiency on neural function is widespread, including its regulation of adult neural stem cell (aNSC) differentiation. To assess FMRP activity, we performed ribosome profiling of aNSCs from normal and Fmr1 knockout mice, which revealed diverse gene expression changes at the mRNA and translation levels. Many mitosis and neurogenesis genes were dysregulated primarily at the mRNA level, while numerous synaptic genes were mostly dysregulated at the translation level. Translational “buffering” was also evident, whereby changes in ribosome association with mRNA is compensated by alterations in RNA abundance. Our data revealed that FMRP-regulated neurogenesis is mediated by the transcriptional factor necdin and that FMRP determines mitochondrial mRNA expression and energy homeostasis. Thus, FMRP controls diverse transcriptional and post-transcriptional gene expression programs critical for the adult neural stem cell differentiation.