Fragile X granules are a family of axonal ribonucleoprotein particles with circuit‐dependent protein composition and mRNA cargos

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The formation and plasticity of neural circuits requires precise spatiotemporal regulation of the neuronal proteome. The importance of this regulation is highlighted by the strong association between dysregulated protein synthesis and cognitive deficits, notably in autism and autism‐related disorders such as PTEN hamartoma syndrome, tuberous sclerosis, and Fragile X syndrome (FXS) (Kelleher & Bear, 2008). FXS is the most common single‐gene form of intellectual disability and autism and is caused by mutations in the gene encoding FMRP (Fragile X mental retardation protein), an RNA‐binding protein that serves as a key regulator of neuronal protein synthesis. Further, common variants in the genes encoding the Fragile X‐related (FXR) proteins FMRP, FXR1P, and FXR2P modify autistic traits in the general population (Stepniak et al., 2015). Loss of FMRP leads to profound changes in synaptic function that are thought to underlie the developmental delay, decreased cognitive function, autism, epilepsy, anxiety, and hypersensitivity to sensory stimuli characteristic of this disorder. Notably, while FXS patients exhibit general developmental delay, not all domains are affected equally (Roberts et al., 2009). Moreover, FXS patients show region‐selective abnormalities in brain morphology and connectivity (Bruno et al., 2017; Hall, Jiang, Reiss, & Greicius, 2013; Hoeft et al., 2010). These findings suggest that FMRP plays circuit‐dependent roles in the regulation of neuronal protein expression.
One mode by which FMRP exerts precise control over the neuronal proteome is by regulating local translation in both the dendritic and axonal arbors. The localization and translation of mRNAs are dependent on their interaction with ribonucleoprotein particles (RNPs), or RNA granules. The brain region‐dependent effects seen in FXS patients raise the possibility that both FMRP‐containing RNPs and the mRNAs that they regulate may differ among circuits. Elucidating how, when and where FMRP‐dependent translational regulation functions in the brain therefore requires determining the protein composition, mRNA cargo and circuit‐selective expression of FMRP‐containing granules. In axons, FMRP and the other FXR proteins localize to discrete, circuit‐selective RNPs termed Fragile X granules (FXGs) (Christie, Akins, Schwob, & Fallon, 2009). FXGs are expressed exclusively in axons that have synaptically integrated into circuits where they associate with ribosomes and mRNA and influence the composition of the axonal proteome (Akins et al., 2017). The circuits that contain FXGs as well as the association of these granules with ribosomes and mRNA are conserved across mice, rats and humans (Akins et al., 2017), suggesting that their study in mice will elucidate axonal translation in the human brain.
Neurons exhibit remarkable circuit‐dependent structural and functional diversity in their axonal arbors. Circuit‐selective expression of axonal RNPs may be one mechanism supporting this diversity. As a first step to address this question, we asked whether FXGs comprise a family of RNPs that differ among neural circuits in their protein composition and mRNA cargoes. We find that FXGs can be classified into four types based on their FXR protein composition. Strikingly, within brain regions, FXG type was homogeneous: most FXGs in each circuit contain the same combination of Fragile X proteins. Although all four FXG types associate with ribosomes and mRNA, the specific mRNA cargoes varied among circuits. The mRNAs encoding β‐catenin and APC (adenomatous polyposis coli) are associated exclusively with forebrain FXGs in select circuits, where both transcripts could be found together within individual FXGs. Together, these findings suggest that FMRP‐regulated axonal translation may mediate distinct cellular roles in different neuronal circuits.
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