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