Fragile <scp>X</scp> granules are a family of axonal ribonucleoprotein particles with circuit‐dependent protein composition and m<scp>RNA</scp> cargos

Chyung, Eunice; LeBlanc, Hannah; Fallon, Justin R.; Akins, Michael R.

doi:10.1002/cne.24321

Cited by 31 publications

(53 citation statements)

References 38 publications

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“…In contrast, neither FMRP nor FXR1P is required as even in wild type brains there are FXG populations that lack one or both of these proteins (Chyung et al, 2018). Instead, an increase in FXG abundance in Fmr1 null mice reveals that FMRP regulates FXG number and the duration of their expression but does not regulate the circuits in which they are found or their structure (Akins et al, 2012(Akins et al, , 2017Christie et al, 2009;Chyung et al, 2018). Wild type FXGs have a characteristic substructure with the protein and RNA components arranged in overlapping but distinct subdomains.…”

Section: Introductionmentioning

confidence: 99%

“…This variety suggests that different mechanisms guide the formation of FMRP-containing RNPs in different parts of the nervous system. Fragile X granules (FXGs) are a class of RNPs that exemplify how cellular context influences the formation and composition of FMRP-containing complexes (Akins et al, 2017;Christie et al, 2009;Chyung et al, 2018). FXGs are only found in axons and are not seen in somata or dendrites, despite the presence of the constituent proteins and mRNAs in these other cellular compartments (Akins et al, 2012(Akins et al, , 2017Christie et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, FXGs are only found in a specific subset of neuronal populations that is stereotyped across individuals and conserved across mammalian species (Akins et al, 2012(Akins et al, , 2017Christie et al, 2009). Notably, the mechanisms governing FXG expression are cell type-dependent as FXGs are homogeneous within each neuronal population but vary across populations in their developmental window of expression, their protein composition, and the mRNAs with which they associate (Akins et al, 2017;Christie et al, 2009;Chyung et al, 2018). All forebrain FXGs contain FMRP along with the Fragile X related (FXR) protein FXR2P while circuit-selective subsets contain the FXR protein FXR1P.…”

Section: Introductionmentioning

confidence: 99%

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FMRP association with and regulation of Fragile X granules exhibit circuit-dependent requirements for the KH2 RNA binding domain

Gingrich

et al. 2018

Preprint

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The localization and translation of mRNAs is controlled by a diverse array of ribonucleoprotein particles (RNPs), multimolecular complexes containing mRNAs and RNA binding proteins. Fragile X granules (FXGs) are a family of RNPs that exemplify the diversity of RNA granules in the mammalian nervous system. FXGs are found in a conserved subset of neurons, where they localize exclusively to the axonal compartment. Notably, the specific RNA binding proteins and mRNAs found in FXGs depend on brain circuit and neuron type, with all forebrain FXGs containing Fragile X mental retardation protein (FMRP), the protein mutated in the human autism-related disorder Fragile X syndrome. FMRP negatively regulates FXG abundance but is not required for their association with ribosomes or mRNA. To better understand the circuitdependent mechanisms whereby FMRP associates with and regulates FXGs, we asked how a disease-causing point mutation, I304N, in the KH2 RNA binding domain of FMRP affects these granules in two brain regionscortex and hippocampus. We found that FMRP I304N had a reduced association with FXGs, as it was absent from approximately half of FXGs in cortex and nearly all FXGs in hippocampus. FXG abundance correlated with the number of FMRPcontaining FXGs, suggesting that FMRP regulates FXG abundance by KH2-independent mechanisms that occur locally within the granules. Together, these findings illustrate that cell type-dependent mechanisms guide the assembly of similar RNA granules. Further, point mutations in RNA granule components may lead to cell type-dependent phenotypes that produce atypical forms of disorders that normally arise from more severe mutations.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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FMRP association with and regulation of Fragile X granules exhibit circuit-dependent requirements for the KH2 RNA binding domain

Gingrich

et al. 2018

Preprint

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“…All three FXR proteins have equivalent RNA binding properties via the KH domains (Darnell et al, 2009). However, FXR2P is unique in being an essential component of Fragile X granules (FXGs), a class of endogenous RNA granules that associate with ribosomes as well as mRNAs that encode proteins important for neuronal plasticity (Fragile X granules;; Christie et al, 2009;; Akins et al, 2017;; Chyung et al, 2018). FXGs are only present in a subset of stereotyped neurons where they are restricted to axonal arbors (Akins et al, 2012;; Akins et al, 2017).…”

Section: Summary Statementmentioning

confidence: 99%

“…FXG subtypes, all containing FXR2P but differing in FMRP/FXR1P and mRNA content, are present in distinct circuits(Christie et al, 2009;; Akins et al, 2017;; Chyung et al, 2018). These results suggest that individual neuronal types contain sets of molecular and/or cellular factors that promote the structural reorganization of FXR2P via its LC and RNA binding domains to assemble FXGs in a circuit-selective fashion.…”

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confidence: 91%

The FXR2P low complexity domain drives assembly of multiple fibril types with differing ribosome association in neurons

Stackpole

Akins

Ivshina

et al. 2018

Preprint

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Axonal localization of the fragile X family of RNA binding proteins is conserved across mammals

Shepard

Korsak

DeBartolo

et al. 2019

J of Comparative Neurology

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Spatial segregation of proteins to neuronal axons arises in part from local translation of mRNAs that are first transported into axons in ribonucleoprotein particles (RNPs), complexes containing mRNAs and RNA binding proteins. Understanding the importance of local translation for a particular circuit requires not only identifying axonal RNPs and their mRNA cargoes, but also whether these RNPs are broadly conserved or restricted to only a few species. Fragile X granules (FXGs) are axonal RNPs containing the fragile X related family of RNA binding proteins along with ribosomes and specific mRNAs. FXGs were previously identified in mouse, rat, and human brains in a conserved subset of neuronal circuits but with species-dependent developmental profiles. Here, we asked whether FXGs are a broadly conserved feature of the mammalian brain and sought to better understand the species-dependent developmental expression pattern. We found FXGs in a conserved subset of neurons and circuits in the brains of every examined species that together include mammalian taxa separated by up to 160 million years of divergent evolution. A developmental analysis of rodents revealed that FXG expression in frontal cortex and olfactory bulb followed consistent patterns in all species examined. In contrast, FXGs in hippocampal mossy fibers increased in abundance across development for most species but decreased across development in guinea pigs and members of the Mus genus, animals that navigate particularly small home ranges in the wild. The widespread conservation of FXGs suggests that axonal translation is an ancient, conserved mechanism for regulating the proteome of mammalian axons. K E Y W O R D S axonal translation, local protein synthesis, RNA binding proteins, RRID AB_10805421, RRID AB_2278530, RRID AB_2737297, RRID AB_528262

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

Cited by 31 publications

References 38 publications

FMRP association with and regulation of Fragile X granules exhibit circuit-dependent requirements for the KH2 RNA binding domain

FMRP association with and regulation of Fragile X granules exhibit circuit-dependent requirements for the KH2 RNA binding domain

The FXR2P low complexity domain drives assembly of multiple fibril types with differing ribosome association in neurons

Axonal localization of the fragile X family of RNA binding proteins is conserved across mammals

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