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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE112502 | GEO | 2018/11/20

REPOSITORIES: GEO

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Project description:Local translation at the synapse plays key roles in neuron development and activity-dependent synaptic plasticity. mRNAs are translocated from the neuronal soma to the distant synapses as compacted ribonucleoparticles referred to as RNA granules. These contain many RNA-binding proteins, including the Fragile X Mental Retardation Protein (FMRP), the absence of which results in Fragile X Syndrome, the most common inherited form of intellectual disability and the leading genetic cause of autism. Using FMRP as a tracer, we purified a specific population of RNA granules from mouse brain homogenates. Protein composition analyses revealed a strong relationship between polyribosomes and RNA granules. However, the latter have distinct architectural and structural properties, since they are detected as close compact structures as observed by electron microscopy, and converging evidence point to the possibility that these structures emerge from stalled polyribosomes. Time-lapse video microscopy indicated that single granules merge to form cargoes that are transported from the soma to distal locations. Transcriptomic analyses showed that a subset of mRNAs involved in cytoskeleton remodelling and neural development is selectively enriched in RNA granules. One third of the putative mRNA targets described for FMRP appear to be transported in granules and FMRP is more abundant in granules than in polyribosomes. This observation supports a primary role for FMRP in granules biology. Our findings open new avenues for the study of RNA granule dysfunctions in animal models of nervous system disorders, such as Fragile X syndrome. Fragile X syndrome is the most common form of inherited mental retardation affecting approximately 1 female out of 7000 and 1 male out of 4000 worldwide. The syndrome is due to the silencing of a single gene, the Fragile Mental Retardation 1 (FMR1), that codes for the Fragile X mental retardation protein (FMRP). This protein is highly expressed in brain and controls local protein synthesis essential for neuronal development and maturation as well as the formation of neural circuits. Several studies suggest a role for FMRP in the regulation of mRNA transport along axons and dendrites to distant synaptic locations in structures called RNA granules. Here we report the isolation of a particular subpopulation of these structures and the analysis of their architecture and composition in terms of RNA and protein. Also, using time-lapse video microscopy, we monitored granule transport and fusion throughout neuronal processes. These findings open new avenues for the study of RNA transport dysfunctions in animal models of nervous system disorders. The control or reference structure or subcellular fraction are the neuronal polyribosomes while the experimental or test structure or subcellular fraction are the neuronal granules. Three independant replicates were done for each structure. Microarray hybridization was done using a two-color design in full dye-swap.

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

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