The FXG: a presynaptic fragile X granule expressed in a subset of developing brain circuits
Open accessAbstract
The loss of Fragile X mental retardation protein (FMRP) causes Fragile X syndrome, the most common inherited mental retardation and single gene cause of autism. Although postsynaptic functions for FMRP are well established, potential roles at the presynaptic apparatus remain largely unexplored. Here, we characterize the expression of FMRP and its homologs, FXR1P and FXR2P, in the developing, mature and regenerating rodent nervous system, with a focus on presynaptic expression. As expected, FMRP is expressed in the somatodendritic domain in virtually all neurons. However, FMRP is also localized in discrete granules (Fragile X granules; FXGs) in a subset of brain regions including frontal cortex, hippocampal area CA3 and olfactory bulb glomeruli. Immunoelectron microscopy shows that FMRP is localized at presynaptic terminals and in axons within these FXG-rich regions. With the exception of the olfactory bulb, FXGs are prominent only in the developing brain. Experiments in regenerating olfactory circuits indicate that peak FXG expression occurs 2–4 weeks after neurogenesis, a period that correlates with synapse formation and refinement. Virtually all FXGs contain FXR2P, while region-selective subsets harbor FMRP and/or FXR1P. Genetic studies show that FXR2P is essential for FXG expression, while FMRP regulates FXG number and developmental profile. These findings suggest that Fragile X proteins play a distinct, presynaptic role during discrete developmental epochs in defined circuits of the mammalian CNS. We propose that the neurological defects in Fragile X syndrome, including the autistic features, could be due in part to the loss of FMRP function in presynaptic compartments.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
FMRP is present in the neuronal cell body, proximal dendrites and axons.
“In the brain, FMRP is present in the neuronal cell body, proximal dendrites and axons (Christie et al., 2009)”
From FMRP Stalls Ribosomal Translocation on mRNAs Linked to Synaptic Function and Autism (2011) · cites this paper as Christie et al., 2009
The bulk of FMRP protein resides in the cell body.
“the bulk of the protein is in the cell body (Christie et al., 2009).”
From FMRP Stalls Ribosomal Translocation on mRNAs Linked to Synaptic Function and Autism (2011) · cites this paper as Christie et al., 2009
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Altered synaptic plasticity in a mouse model of fragile X mental retardation
Huber, K. M., Gallagher, S. M., Warren, S. T., & Bear, M. F. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.122205699 · Cited by 1,349 · see citing works
Evidence of Brain Overgrowth in the First Year of Life in Autism
Courchesne, E. (2003) · JAMA · doi:10.1001/jama.290.3.337 · Cited by 1,120 · see citing works
Brown, V., Jin, P., Ceman, S., Darnell, J. C., O'Donnell, W. T., Tenenbaum, S. A., Jin, X., Feng, Y., Wilkinson, K. D., Keene, J. D., et al. (2001) · Cell · doi:10.1016/s0092-8674(01)00568-2 · Cited by 1,109 · see citing works
An autoradiographic analysis of histogenesis in the mouse cerebellum
Miale, I. L., & Sidman, R. L. (1961) · Experimental Neurology · doi:10.1016/0014-4886(61)90055-3 · Cited by 1,015 · see citing works
Graziadei, P. P. C., & Graziadei, G. A. M. (1979) · Journal of Neurocytology · doi:10.1007/bf01206454 · Cited by 1,006 · see citing works
Harris, K. M., Jensen, F. E., & Tsao, B. (1992) · Journal of Neuroscience · doi:10.1523/jneurosci.12-07-02685.1992 · Cited by 990 · see citing works
Devys, D., Lutz, Y., Rouyer, N., Bellocq, J., & Mandel, J. (1993) · Nature Genetics · doi:10.1038/ng0893-335 · Cited by 781 · see citing works
Synaptogenesis Via Dendritic Filopodia in Developing Hippocampal Area CA1
Fiala, J. C., Feinberg, M., Popov, V., & Harris, K. M. (1998) · The Journal of Neuroscience · doi:10.1523/jneurosci.18-21-08900.1998 · Cited by 758 · see citing works
Identifying autism loci and genes by tracing recent shared ancestry
Morrow, E. M., Yoo, S.-Y., Flavell, S. W., Kim, T.-K., Lin, Y., Hill, R. S., Mukaddes, N. M., Balkhy, S., Gascon, G., Hashmi, A., et al. (2008) · Science · doi:10.1126/science.1157657 · Cited by 737 · see citing works
Schlessinger, A. R., Cowan, W. M., & Gottlieb, D. I. (1975) · The Journal of Comparative Neurology · doi:10.1002/cne.901590202 · Cited by 731 · see citing works
Postnatal neurodevelopmental disorders: meeting at the synapse?
Zoghbi, H. Y. (2003) · Science · doi:10.1126/science.1089071 · Cited by 691 · see citing works
Sloviter, R. S. (1989) · The Journal of Comparative Neurology · doi:10.1002/cne.902800203 · Cited by 686 · see citing works
Zhang, Y., Bailey, A. M., Matthies, H. J. G., Renden, R., Smith, M. A., Speese, S. D., Rubin, G. M., & Broadie, K. S. (2001) · Cell · doi:10.1016/s0092-8674(01)00589-x · Cited by 641 · see citing works
Altman, J. (1969) · The Journal of Comparative Neurology · doi:10.1002/cne.901360303 · Cited by 630 · see citing works
The Fragile X Syndrome Protein Represses Activity-Dependent Translation through CYFIP1, a New 4E-BP
Napoli, I., Mercaldo, V., Boyl, P. P., Eleuteri, B., Zalfa, F., De Rubeis, S., Di Marino, D., Mohr, E., Massimi, M., Falconi, M., et al. (2008) · Cell · doi:10.1016/j.cell.2008.07.031 · Cited by 609 · see citing works
Jin, P., Zarnescu, D. C., Ceman, S., Nakamoto, M., Mowrey, J., Jongens, T. A., Nelson, D. L., Moses, K., & Warren, S. T. (2004) · Nature Neuroscience · doi:10.1038/nn1174 · Cited by 604 · see citing works
Learning and Memory and Synaptic Plasticity Are Impaired in a Mouse Model of Rett Syndrome
Moretti, P., Levenson, J. M., Battaglia, F., Atkinson, R., Teague, R., Antalffy, B., Armstrong, D., Arancio, O., Sweatt, J. D., & Zoghbi, H. Y. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.2623-05.2006 · Cited by 545 · see citing works
Feng, Y., Gutekunst, C.-A., Eberhart, D. E., Yi, H., Warren, S. T., & Hersch, S. M. (1997) · The Journal of Neuroscience · doi:10.1523/jneurosci.17-05-01539.1997 · Cited by 532 · see citing works
MRI volumes of amygdala and hippocampus in non–mentally retarded autistic adolescents and adults
Aylward, E., Minshew, N. J., Goldstein, G., Honeycutt, N. A., Augustine, A. M., Yates, K. O., Barta, P. E., & Pearlson, G. D. (1999) · Neurology · doi:10.1212/wnl.53.9.2145 · Cited by 513 · see citing works
MeCP2 Controls Excitatory Synaptic Strength by Regulating Glutamatergic Synapse Number
Chao, H.-T., Zoghbi, H. Y., & Rosenmund, C. (2007) · Neuron · doi:10.1016/j.neuron.2007.08.018 · Cited by 511 · see citing works
RNA cargoes associating with FMRP reveal deficits in cellular functioning in Fmr1 null mice
Miyashiro, K. Y., Beckel-Mitchener, A., Purk, T. P., Becker, K. G., Barret, T., Liu, L., Carbonetto, S., Weiler, I. J., Greenough, W. T., & Eberwine, J. (2003) · Neuron · doi:10.1016/s0896-6273(03)00034-5 · Cited by 495 · see citing works
A Decade of Molecular Studies of Fragile X Syndrome
O'Donnell, W. T., & Warren, S. T. (2002) · Annual Review of Neuroscience · doi:10.1146/annurev.neuro.25.112701.142909 · Cited by 481 · see citing works
Bayer, S. A., & Altman, J. (1974) · Journal of Comparative Neurology · doi:10.1002/cne.901580105 · Cited by 344 · see citing works
Axonal Wiring in the Mouse Olfactory System
Mombaerts, P. (2006) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.21.012804.093915 · Cited by 308 · see citing works
Nosyreva, E. D., & Huber, K. M. (2006) · Journal of Neurophysiology · doi:10.1152/jn.01316.2005 · Cited by 292 · see citing works
Intra-axonal translation and retrograde trafficking of CREB promotes neuronal survival
Cox, L. J., Hengst, U., Gurskaya, N. G., Lukyanov, K. A., & Jaffrey, S. R. (2008) · Nature Cell Biology · doi:10.1038/ncb1677 · Cited by 273 · see citing works
Extracellular stimuli specifically regulate localized levels of individual neuronal mRNAs
Willis, D. E., van Niekerk, E. A., Sasaki, Y., Mesngon, M. T., Merianda, T. T., Williams, G. G., Kendall, M., Smith, D. S., Bassell, G. J., & Twiss, J. L. (2007) · The Journal of Cell Biology · doi:10.1083/jcb.200703209 · Cited by 270 · see citing works
Reconstitution of the rat olfactory epithelium after methyl bromide‐induced lesion
Schwob, J. E., Youngentob, S. L., & Mezza, R. C. (1995) · The Journal of Comparative Neurology · doi:10.1002/cne.903590103 · Cited by 267 · see citing works
Self-citationAntar, L. N., Li, C., Zhang, H., Carroll, R. C., & Bassell, G. J. (2006) · Molecular and Cellular Neuroscience · doi:10.1016/j.mcn.2006.02.001 · Cited by 259 · see citing works
Corbin, F. (1997) · Human Molecular Genetics · doi:10.1093/hmg/6.9.1465 · Cited by 235 · see citing works
Huang, Y., Kan, M.-C., Lin, C., & Richter, J. D. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601322 · Cited by 229 · see citing works
Shepherd, G. M., Chen, W. R., & Greer, C. A. (2004) · Oxford University Press eBooks · doi:10.1093/acprof:oso/9780195159561.003.0005 · Cited by 216 · see citing works
Localized Synaptic Potentiation by BDNF Requires Local Protein Synthesis in the Developing Axon
Zhang, X.-H., & Poo, M. (2002) · Neuron · doi:10.1016/s0896-6273(02)01023-1 · Cited by 209 · see citing works
Immunocytochemical and Biochemical Characterization of FMRP, FXR1P, and FXR2P in the Mouse
Bakker, C. E., de Diego‐Otero, Y., Bontekoe, C. J. M., Raghoe, P., Luteijn, T., Hoogeveen, A. T., Oostra, B. A., & Willemsen, R. (2000) · Experimental Cell Research · doi:10.1006/excr.2000.4932 · Cited by 193 · see citing works
Nosyreva, E. D., & Huber, K. M. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.3652-04.2005 · Cited by 182 · see citing works
Abnormal Striatal GABA Transmission in the Mouse Model for the Fragile X Syndrome
Centonze, D., Rossi, S., Mercaldo, V., Napoli, I., Ciotti, M. T., De Chiara, V., Musella, A., Prosperetti, C., Calabresi, P., Bernardi, G., et al. (2008) · Biological Psychiatry · doi:10.1016/j.biopsych.2007.09.008 · Cited by 171 · see citing works
Michel, C. I., Kraft, R., & Restifo, L. L. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.1102-04.2004 · Cited by 145 · see citing works
Odorant Receptor Expression Patterns Are Restored in Lesion-Recovered Rat Olfactory Epithelium
Iwema, C. L., Fang, H., Kurtz, D. B., Youngentob, S. L., & Schwob, J. E. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.1219-03.2004 · Cited by 145 · see citing works
Self-citationFunction and regulation of local axonal translation
Lin, A. C., & Holt, C. E. (2008) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2008.05.004 · Cited by 144 · see citing works
mRNPs, polysomes or granules: FMRP in neuronal protein synthesis
Zalfa, F., Achsel, T., & Bagni, C. (2006) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2006.05.010 · Cited by 138 · see citing works
Fxr1 knockout mice show a striated muscle phenotype: implications for Fxr1p function in vivo
Mientjes, E. (2004) · Human Molecular Genetics · doi:10.1093/hmg/ddh150 · Cited by 132 · see citing works
The Neuropathology of Autism: A Review
Pickett, J., & London, E. (2005) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/01.jnen.0000186921.42592.6c · Cited by 122 · see citing works
Knockout mouse model for Fxr2: a model for mental retardation
Bontekoe, C. J. M. (2002) · Human Molecular Genetics · doi:10.1093/hmg/11.5.487 · Cited by 120 · see citing works
Synapse Formation and mRNA Localization in Cultured Aplysia Neurons
Lyles, V., Zhao, Y., & Martin, K. C. (2006) · Neuron · doi:10.1016/j.neuron.2005.12.029 · Cited by 114 · see citing works
Gabel, L. A., Won, S., Kawai, H. D., McKinney, M., Tartakoff, A. M., & Fallon, J. R. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.2185-04.2004 · Cited by 103 · see citing works
Self-citationDevelopment and organization of ocular dominance bands in primary visual cortex of the sable ferret
Ruthazer, E. S., Baker, G. E., & Stryker, M. P. (1999) · The Journal of Comparative Neurology · doi:10.1002/(sici)1096-9861(19990503)407:2 · Cited by 46 · see citing works
Markers of mRNA stabilization and degradation, and RNAi within astrocytoma GW bodies
Moser, J. J., Eystathioy, T., Chan, E. K. L., & Fritzler, M. J. (2007) · Journal of Neuroscience Research · doi:10.1002/jnr.21439 · Cited by 42 · see citing works
Landis, D. M. D. (1987) · The Journal of Comparative Neurology · doi:10.1002/cne.902600405 · Cited by 38 · see citing works
Fragile X syndrome, the Fragile X related proteins, and animal models
Hoogeveen, A. T., Willemsen, R., & Oostra, B. A. (2002) · Microscopy Research and Technique · doi:10.1002/jemt.10064 · Cited by 37 · see citing works
A Panel of Monoclonal Antibodies to Cytoplasmic GW Bodies and the mRNA Binding Protein GW182
Eystathioy, T., Chan, E. K. L., Mähler, M., et al. (2003) · Hybridoma and Hybridomics · doi:10.1089/153685903321947996 · Cited by 34 · see citing works
Development and Characterization of Antibodies that Immunoprecipitate the FMR1 Protein
Ceman, S., Zhang, F., Johnson, T., et al. (2003) · Neurogenetics · doi:10.1385/1-59259-330-5:345 · Cited by 11 · see citing works
Defelipe (1999) · doi:10.1002/(sici)1096-9861(19990927)412:3
Irwin (2001) · doi:10.1002/1096-8628(20010115)98:2
Flagged first, then by citations
Cited by
Sorted by citations
FMRP Stalls Ribosomal Translocation on mRNAs Linked to Synaptic Function and Autism
Darnell, J. C., Van Driesche, S. J., Zhang, C., Hung, K. Y. S., Mele, A., Fraser, C. E., Stone, E. F., Chen, C., Fak, J. J., Chi, S. W., et al. (2011) · Cell · doi:10.1016/j.cell.2011.06.013 · Cited by 2,072 · see citing works
The translation of translational control by FMRP: therapeutic targets for FXS
Darnell, J. C., & Klann, E. (2013) · Nature Neuroscience · doi:10.1038/nn.3379 · Cited by 491 · see citing works
Deng, P.-Y., Rotman, Z., Blundon, J. A., Cho, Y., Cui, J., Cavalli, V., Zakharenko, S. S., & Klyachko, V. A. (2013) · Neuron · doi:10.1016/j.neuron.2012.12.018 · Cited by 354 · see citing works
CGG repeat in the FMR1 gene: size matters
Willemsen, R., Levenga, J., & Oostra, B. (2011) · Clinical Genetics · doi:10.1111/j.1399-0004.2011.01723.x · Cited by 184 · see citing works
RNA Protein Interaction in Neurons
Darnell, R. B. (2013) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-062912-114322 · Cited by 181 · see citing works
Gross, C., Yao, X., Pong, D. L., Jeromin, A., & Bassell, G. J. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.6661-10.2011 · Cited by 161 · see citing works
Myrick, L. K., Deng, P.-Y., Hashimoto, H., Oh, Y. M., Cho, Y., Poidevin, M. J., Suhl, J. A., Visootsak, J., Cavalli, V., Jin, P., et al. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1423094112 · Cited by 133 · see citing works
Till, S. M., Asiminas, A., Jackson, A. D., Katsanevaki, D., Barnes, S. A., Osterweil, E. K., Bear, M. F., Chattarji, S., Wood, E. R., Wyllie, D. J. A., et al. (2015) · Human Molecular Genetics · doi:10.1093/hmg/ddv299 · Cited by 109 · see citing works
Update on the implication of potassium channels in autism: K+ channelautism spectrum disorder
Guglielmi, L. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00034 · Cited by 89 · see citing works
Hyperexcitability and homeostasis in fragile X Syndrome.
Liu, X., Kumar, V., Tsai, N.-P., & Auerbach, B. D. (2022) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2021.805929 · Cited by 53 · see citing works
Choi, C. H., Schoenfeld, B. P., Bell, A. J., Hinchey, J., Rosenfelt, C., Gertner, M. J., Campbell, S. R., Emerson, D., Hinchey, P., Kollaros, M., et al. (2016) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2016.00136 · Cited by 46 · see citing works
Defects in translational regulation contributing to human cognitive and behavioral disease
Darnell, J. (2011) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2011.05.002 · Cited by 43 · see citing works
Wang, Y., Sakano, H., Beebe, K., Brown, M. R., de Laat, R., Bothwell, M., Kulesza, R. J., & Rubel, E. W. (2014) · Journal of Comparative Neurology · doi:10.1002/cne.23520 · Cited by 40 · see citing works
Heads‐up: New roles for the fragile X mental retardation protein in neural stem and progenitor cells
Callan, M. A., & Zarnescu, D. C. (2011) · genesis · doi:10.1002/dvg.20745 · Cited by 39 · see citing works
- Authors
- Christie, S. B., Akins, M. R., Schwob, J. E., & Fallon, J. R.
- Affiliations
- Brown University (US)
- Tufts University (US)
- Corresponding author
- Fallon, Justin R.
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2009-02-04
- Volume
- 29
- Issue
- 5
- Pages
- 1514-1524
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC2746438
- OpenAlex
- W2013080889
- Cited by
- 208
- References
- 53
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 8 · 2023: 11 · 2022: 7 · 2021: 14 · 2020: 18 · 2019: 11 · 2018: 12 · 2017: 12 · 2016: 16 · 2015: 13 · 2014: 13 · 2013: 21 · 2012: 11
- FWCI
- 8.91
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute on Aging (AG 02049, T32AG020498)
- National Institute on Drug Abuse (F32DA021501, DA021501)
- National Institute on Deafness and Other Communication Disorders (R01DC002167, DC002167)
- National Institute of Neurological Disorders and Stroke (P01NS039321)
- National Center for Research Resources (P20RR015578)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD052083, HD052083)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Keywords
- fragile X syndrome, FMRP, FXR1P, presynaptic localization, synaptogenesis, synapse refinement, olfactory bulb, hippocampal CA3, frontal cortex, axons, nervous system regeneration, neurogenesis, autism spectrum disorder, intellectual disability, brain development
- MeSH terms
- Animals, Brain, Frontal Lobe, Hippocampus, Humans, Male, Mice, Inbred C57BL, Nerve Net, Olfactory Bulb, Rats, Sprague-Dawley, Presynaptic Terminals, Mice, Knockout, Gene Expression Regulation, Developmental, Mice, Rats, Fragile X Messenger Ribonucleoprotein 1, Neurogenesis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
