Cited by 644Genetics and Neurodevelopmental DisordersNeuroscience and Neuropharmacology ResearchRNA and protein synthesis mechanisms

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Fragile X mental retardation protein is translated near synapses in response to neurotransmitter activation

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Weiler, Ivan Jeanne, Irwin, Scott A., Klintsova, Anna Y., Spencer, Corinne M., Brazelton, Anthony D., Miyashiro, Kevin, Comery, Thomas A., Patel, Bindu, Eberwine, James, Greenough, William T.·1997·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.94.10.5395PMC PMC24689

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Abstract

Local translation of proteins in distal dendrites is thought to support synaptic structural plasticity. We have previously shown that metabotropic glutamate receptor (mGluR1) stimulation initiates a phosphorylation cascade, triggering rapid association of some mRNAs with translation machinery near synapses, and leading to protein synthesis. To determine the identity of these mRNAs, a cDNA library produced from distal nerve processes was used to screen synaptic polyribosome-associated mRNA. We identified mRNA for the fragile X mental retardation protein (FMRP) in these processes by use of synaptic subcellular fractions, termed synaptoneurosomes. We found that this mRNA associates with translational complexes in synaptoneurosomes within 1-2 min after mGluR1 stimulation of this preparation, and we observed increased expression of FMRP after mGluR1 stimulation. In addition, we found that FMRP is associated with polyribosomal complexes in these fractions. In vivo, we observed FMRP immunoreactivity in spines, dendrites, and somata of the developing rat brain, but not in nuclei or axons. We suggest that rapid production of FMRP near synapses in response to activation may be important for normal maturation of synaptic connections.

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Background
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Result
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Background
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Todd, P. K., Malter, J. S., & Mack, K. J. (2003) · Molecular Brain Research · doi:10.1016/s0169-328x(02)00657-5 · Cited by 56
“5, 20 min dent event [24,53,58].”
BackgroundMethodResultInfluential
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Background
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Background
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Background
Cytoplasmic Polyadenylation Element Binding Protein 1-Mediated mRNA Translation in Purkinje Neurons Is Required for Cerebellar Long-Term Depression and Motor Coordination
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Background
A Functional Requirement for PAK1 Binding to the KH(2) Domain of the Fragile X Protein-Related FXR1
Say, E. H. M., Tay, H.-G., Zhao, Z.-S., Baskaran, Y., Li, R., Lim, L., & Manser, E. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.04.004 · Cited by 51
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Background
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Background
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Background
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Background
Fragile X Mental Retardation Protein in Learning-Related Synaptic Plasticity
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BackgroundInfluential
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Background
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Background
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Background
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Background
Partial FMRP expression is sufficient to normalize neuronal hyperactivity in Fragile X neurons
Graef, J. D., Wu, H., Ng, C., Sun, C., Villegas, V., Qadir, D., Jesseman, K., Warren, S. T., Jaenisch, R., Cacace, A. M., et al. (2019) · European Journal of Neuroscience · doi:10.1111/ejn.14660 · Cited by 42
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Background
Post-translational modifications of the Fragile X Mental Retardation Protein in neuronal function and dysfunction
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Development and Behavior of Male Toddlers With Fragile X Syndrome
Roberts, J. E., Hatton, D. D., & Bailey, D. B. (2001) · Journal of Early Intervention · doi:10.1177/10538151010240030601 · Cited by 40
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“E-mail: d.loesch@latrobe.edu.au Received 17 July 2001; Accepted 6 September 2002 DOI 10.1002/ajmg.a.10099 2003 Wiley-Liss, Inc. cerebral cortex, cerebellum, and hippocampus [Witt et al., 1995], and in modifying synaptic structure [Weiler et al., 1997; Weiler and Greenough, 1999].”
BackgroundInfluential
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“In addition, FMRP plays an essential role in synapse development (Weiler et al., 1997), which is vital for proper neurotransmission, learning and memory, and synaptic plasticity.”
Background
Identification of developmental disorders including autism spectrum disorder using salivary miRNAs in children from Bosnia and Herzegovina
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Depolarization-induced translocation of the RNA-binding protein Sam68 to the dendrites of hippocampal neurons
Fredj, N. B., Grange, J., Sadoul, R., Richard, S., Goldberg, Y., & Boyer, V. (2004) · Journal of Cell Science · doi:10.1242/jcs.00927 · Cited by 40
“, 1998), or FMRP (fragile X mental retardation protein) (Weiler et al., 1997) are”
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Analysis of proteins that rapidly change upon mechanistic/mammalian target of rapamycin complex 1 (mTORC1) repression identifies parkinson protein 7 (PARK7) as a novel protein aberrantly expressed in tuberous sclerosis complex (TSC)
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“Related ﬁ ndings can be loosely organized according to whether they mainly addresses trans-membrane elements (AMPARs, NMDARs, VGCCs, GPCRs), primary signalling molecules other than glutamate (DA, ACh, NE, 5-HT, BDNF, TNF, eCBs), intracellular molecular players (Ca 2 + , cAMP, CaMKII, PKA, PKC, PKM ζ , IP3), or modulat…”
BackgroundInfluential
Review of targeted treatments in fragile X syndrome
Ligsay, A., & Hagerman, R. J. (2016) · Intractable & Rare Diseases Research · doi:10.5582/irdr.2016.01045 · Cited by 38
Fragile X Mental Retardation Protein Regulates Activity-Dependent Membrane Trafficking and Trans-Synaptic Signaling Mediating Synaptic Remodeling
Sears, J. C., & Broadie, K. S. (2018) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2017.00440 · Cited by 35
“FMRP is directly regulated by activity (Weiler et al., 1997; Antar et al., 2004) and, in turn, regulates activity-dependent processes (Huber et al., 2002; Li et al., 2002).”
Background
The Fragile X Mental Retardation Protein in Circadian Rhythmicity and Memory Consolidation
Gatto, C. L., & Broadie, K. S. (2009) · Molecular Neurobiology · doi:10.1007/s12035-009-8057-0 · Cited by 38
“Early in vitro studies revealed that FMRP is translated upon the protein synthesis induction mediated by mGluR activation [29, 115].”
Background
Lithium: A Promising Treatment for Fragile X Syndrome
Liu, Z., & Smith, C. B. (2014) · ACS Chemical Neuroscience · doi:10.1021/cn500077p · Cited by 39
Tissue and developmental regulation of fragile X mental retardation 1 exon 12 and 15 isoforms
Xie, W. Q., Dolzhanskaya, N., LaFauci, G., Dobkin, C., & Denman, R. B. (2009) · Neurobiology of Disease · doi:10.1016/j.nbd.2009.03.015 · Cited by 37
“Several lines of evidence point to a prominent role for FMRP in regulating synapse dynamics via modulation of local protein synthesis in synaptodendritic compartments of neurons (Antar et al., 2004; Antar et al., 2006; Hou et al., 2006; Pfeiffer and Huber, 2007; Weiler et al., 1997).”
Background
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 36
“…the basis of these pathological findings, combined with the observation that glutamate receptor stimulation of preparations of synaptosomes leads to a rapid increase in the synthesis of FMRP, it was postulated that FMRP is directly involved in synapse maturation and function (Weiler et al., 1997).”
Roles of Calcium-Stimulated Adenylyl Cyclase and Calmodulin-Dependent Protein Kinase IV in the Regulation of FMRP by Group I Metabotropic Glutamate Receptors
Wang, H., Wu, L., Zhang, F.-X., & Zhuo, M. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.0646-08.2008 · Cited by 37
“FMRP is likely to be critically involved in the biochemical regulation of translation during mGluR activation (Weiler et al., 1997; Antar et al., 2004; Hou et al., 2006).”
Background
Determinants of Ictal Epileptiform Patterns in the Hippocampal Slice
Rutecki, P. A., Sayın, Ü., Yang, Y., & Hadar, E. J. (2002) · Epilepsia · doi:10.1046/j.1528-1157.43.s.5.34.x · Cited by 36
“Furthermore, group I mGluR activation leads to activation of protein synthesis of the fragile X–related protein that modulates local protein synthesis in the dendrite (28).”
Repeat-mediated epigenetic dysregulation of the FMR1 gene in the fragile X-related disorders
Usdin, K., & Kumari, D. (2015) · Frontiers in Genetics · doi:10.3389/fgene.2015.00192 · Cited by 35
Mental retardation genes in drosophila: New approaches to understanding and treating developmental brain disorders
Restifo, L. L. (2005) · Mental Retardation and Developmental Disabilities Research Reviews · doi:10.1002/mrdd.20083 · Cited by 35
“Activation of metabotropic glutamate receptors (mGluR), specifically the Gp1 class, regulates FMRP localization and perisynaptic translation [Weiler et al., 1997, 2004; Todd et al., 2003; Antar et al., 2004].”
The gene encoding the fragile X RNA-binding protein is controlled by nuclear respiratory factor 2 and the CREB family of transcription factors
Smith, K. T. (2006) · Nucleic Acids Research · doi:10.1093/nar/gkj521 · Cited by 34
“For example, FMR1 mRNA and FMRP rapidly localize in dendrites in response to treatment with KCl and FMRP is quickly translated within 5 min of mGluR stimulation of neurons (56,57).”
Background
Fragile X syndrome and model organisms: identifying potential routes of therapeutic intervention
Bhogal, B., & Jongens, T. A. (2010) · Disease Models & Mechanisms · doi:10.1242/dmm.002006 · Cited by 36
“Several studies from William Greenough’s group determined that mRNA encoding FMRP is enriched in the postsynaptic compartment of synapses and is rapidly translated in response to mGluR stimulation (Weiler et al., 1997; Weiler and Greenough, 1999).”
Background
Transport kinetics of FMRP containing the I304N mutation of severe fragile X syndrome in neurites of living rat PC12 cells
Schrier, M., Severijnen, L., Reis, S. A., Rife, M. F., VANTPADJE, S., VANCAPPELLEN, G., Oostra, B. A., & Willemsen, R. (2004) · Experimental Neurology · doi:10.1016/j.expneurol.2004.05.039 · Cited by 34
Drosophila as a Tool for Personalized Medicine: A Primer
Kasai, Y., & Cagan, R. L. (2010) · Personalized Medicine · doi:10.2217/pme.10.65 · Cited by 34
“A common form of mental retardation, Fragile X is linked to alterations in the Fragile X mental retardation protein (FMRP), which likely leads to excess glutamate production [63–65].”
Background
MGluRs regulate the expression of neuronal calcium sensor proteins NCS-1 and VILIP-1 and the immediate early gene arg3.1/arc in the hippocampus in vivo
Brackmann, M., Zhao, C., Kuhl, D., Manahan‐Vaughan, D., & Braunewell, K. (2004) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2004.08.028 · Cited by 33
Limbic Epileptogenesis in a Mouse Model of Fragile X Syndrome
Qiu, L.-F., Lu, T., Hu, X.-L., Yi, Y., Liao, W., & Xiong, Z. (2008) · Cerebral Cortex · doi:10.1093/cercor/bhn163 · Cited by 33
“FMRP is upregulated in response to neuronal activity (Weiler et al. 1997; Todd and Mack 2000; Todd et al. 2003; Cerebral Cortex July 2009, V 19 N 7 1511 Gabel et al. 2004; Irwin et al. 2005; Hou et al. 2006) and plays an important role in synaptic plasticity by regulating the translation,…”
BackgroundMethodInfluential
Molecular Insights into Mental Retardation: Multiple Functions for the Fragile X Mental Retardation Protein?
Zalfa, F., & Bagni, C. (2004) · Current Issues in Molecular Biology · doi:10.21775/cimb.006.073 · Cited by 33
“It has been shown that FMR1 mRNA is present in synaptoneurosomes and the synaptic level of FMRP increases following administration of specific mGluRspecific agonists (Weiler et al., 1997).”
Background
Pharmacotherapy for Fragile X Syndrome: Progress to Date
Davenport, M. H., Schaefer, T. L., Friedmann, K., Fitzpatrick, S. E., & Erickson, C. A. (2016) · Drugs · doi:10.1007/s40265-016-0542-y · Cited by 33
Fragile X and APP: a Decade in Review, a Vision for the Future
Westmark, C. J. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-1344-x · Cited by 31
A 3′ untranslated region variant in FMR1 eliminates neuronal activity-dependent translation of FMRP by disrupting binding of the RNA-binding protein HuR
Suhl, J. A., Muddashetty, R. S., Anderson, B. R., Ifrim, M. F., Visootsak, J., Bassell, G. J., & Warren, S. T. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1514260112 · Cited by 33
“These molecular defects are associated with impaired synaptic plasticity, widely believed to underlie the processes of learning and memory, which requires tightly controlled synaptic protein synthesis (16, 17) and is thought to be a principal cause of the cognitive disabilities in FXS patients (12, 18, 19).”
Background
Novel Features of dFMR1, the Drosophila Orthologue of the Fragile X Mental Retardation Protein
Schenck, A., Bor, V. V. D., Bardoni, B., & Giangrande, A. (2002) · Neurobiology of Disease · doi:10.1006/nbdi.2002.0510 · Cited by 31
“Evidence that FMRP can act as a translational regulator (Laggerbauer et al., 2001; Li et al., 2001; Brown et al., 2001; Darnell et al., 2001) notably at the level of neuronal synapses (Weiler et al., 1997; Greenough et al., 2001) is currently accumulating.”
Background
Dissecting the Genetics of Autism Spectrum Disorders: A Drosophila Perspective
Bellosta, P., & Soldano, A. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.00987 · Cited by 32
Localization of mRNAs at Synaptic Sites on Dendrites
Steward, O., & Worley, P. F. (2001) · Results and problems in cell differentiation · doi:10.1007/978-3-540-40025-7_1 · Cited by 30
“This evidence has led to the interesting idea that the neuronal dysfunction that is part of fragile X syndrome may result from a disruption of local synthesis of protein at synapses (Comery et al. 1997; Weiler et al. 1997).”
BackgroundMethod
Dual Regulation of Fragile X Mental Retardation Protein by Group I Metabotropic Glutamate Receptors Controls Translation-Dependent Epileptogenesis in the Hippocampus
Zhao, W., Chuang, S.-C., Bianchi, R., & Wong, R. K. S. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.2915-10.2011 · Cited by 29
“Conversely, group I mGluR stimulation also upregulates FMRP by activating its synthesis (Weiler et al., 1997; Todd et al., 2003a,b; Hou et al., 2006; Zhong et al., 2009).”
BackgroundMethodInfluential
Fragile X mental retardation protein recognition of G quadruplex structure per se is sufficient for high affinity binding to RNA
Bole, M., Menon, L., & Mihailescu, M. (1900) · Molecular BioSystems · doi:10.1039/b812537f · Cited by 29
Neuronal activity drives FMRP- and HSPG-dependent matrix metalloproteinase function required for rapid synaptogenesis
Dear, M. L., Shilts, J., & Broadie, K. (2017) · Science Signaling · doi:10.1126/scisignal.aan3181 · Cited by 29
Development of mavoglurant and its potential for the treatment of fragile X syndrome
Gomez‐Mancilla, B., Berry‐Kravis, E., Hagerman, R. J., von Raison, F., Apostol, G., Ufer, M., Gasparini, F., & Jacquemont, S. (2013) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.2014.857400 · Cited by 30
“However, these problems occur through a different mechanism from the FMRP deficiency in FXS.”
Influential
FMRP Modulates Activity-Dependent Spine Plasticity by Binding Cofilin1 mRNA and Regulating Localization and Local Translation
Feuge, J., Scharkowski, F., Michaelsen‐Preusse, K., & Körte, M. (2019) · Cerebral Cortex · doi:10.1093/cercor/bhz059 · Cited by 28
Mouse models of fragile X-related disorders
Willemsen, R., & Kooy, R. F. (2023) · Disease Models & Mechanisms · doi:10.1242/dmm.049485 · Cited by 30
Molecular-clinical spectrum of the ATR-X syndrome
Gibbons, R. J., & Higgs, D. R. (2000) · American Journal of Medical Genetics · doi:10.1002/1096-8628(200023)97:3 · Cited by 240
Premutation in the Fragile X Mental Retardation 1 (FMR1) Gene Affects Maternal Zn-milk and Perinatal Brain Bioenergetics and Scaffolding
Napoli, E., Ross‐Inta, C., Song, G., Wong, S., Hagerman, R. J., Gane, L. W., Smilowitz, J. T., Tassone, F., & Giulivi, C. (2016) · Frontiers in Neuroscience · doi:10.3389/fnins.2016.00159 · Cited by 28
“Indeed, Shank3 transcript—as actin transcript— has been identified as one of the main mRNAs interacting with FMRP (Darnell et al., 2011) and both FMRP and FMR1 mRNA are normally present in ribosomes associated to postsynaptic dendritic sites, location shared by Shank3 (Weiler et al., 1997).”
Background
Chapter 4 Cap-dependent translation initiation and memory
Banko, J. L., & Klann, E. (2008) · Progress in brain research · doi:10.1016/s0079-6123(07)00004-0 · Cited by 27
Genetic effects on human cognition: lessons from the study of mental retardation syndromes
Nokelainen, P. T. (2002) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp.72.3.287 · Cited by 27
Balanced actions of protein synthesis and degradation in memory formationPreprint
Park, H., & Kaang, B. (2019) · Learning & Memory · doi:10.1101/lm.048785.118 · Cited by 26
“…learning stimuli could transiently increase the expression and dendritic localization of FMRP via metabotropic glutamate recep- tor (mGluR) signaling (Weiler et al. 1997; Irwin et al. 2000; Gabel et al. 2004), suggesting that the FMRP protein plays a role in longterm synaptic plasticity and memory…”
Background
Metabotropic Glutamate Receptor and Fragile X Signaling in a Female Model of Escalated Aggression
Been, L. E., Moore, K. M., Kennedy, B. C., & Meisel, R. L. (2015) · Biological Psychiatry · doi:10.1016/j.biopsych.2015.07.021 · Cited by 26
Experimental identification of microRNA targets on the 3′ untranslated region of human FMR1 gene
Yi, Y., Sun, X., Qin, J.-M., Zhao, Q.-H., Liao, W., & Long, Y. (2010) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2010.04.022 · Cited by 26
Olfactory discrimination learning in mice lacking the fragile X mental retardation protein
Larson, J., Kim, D., Patel, R. C., & Floreani, C. V. (2008) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2008.01.002 · Cited by 26
“In isolated synaptoneurosome preparations, stimulation of metabotropic glutamate receptors (mGluRs) increases FMRP synthesis by activating its local translation (Weiler et al., 1997; Muddashetty et al., 2007; Todd, Mack, & Malter, 2003).”
Background
State‐of‐the‐art therapies for fragile X syndrome
Protic, D. D., & Hagerman, R. J. (2024) · Developmental Medicine & Child Neurology · doi:10.1111/dmcn.15885 · Cited by 25
Amygdala Regulation of Fear and Emotionality in Fragile X Syndrome
Olmos-Serrano, J. L., & Corbin, J. G. (2011) · Developmental Neuroscience · doi:10.1159/000329424 · Cited by 25
Developmental expression of the fragile X-related 1 proteins in mouse testis: association with microtubule elements
Huot, M. (2001) · Human Molecular Genetics · doi:10.1093/hmg/10.24.2803 · Cited by 25
“This could also be the case for FMRP that has been detected in the synaptosomes at distant locations from the neuron body (51).”
Background
NMDAR mediated translation at the synapse is regulated by MOV10 and FMRP
Kute, P. M., Ramakrishna, S., Neelagandan, N., Chattarji, S., & Muddashetty, R. S. (2019) · Molecular Brain · doi:10.1186/s13041-019-0473-0 · Cited by 24

Authors: Weiler, I. J., Irwin, S. A., Klintsova, A. Y., Spencer, C. M., Brazelton, A. D., Miyashiro, K., Comery, T. A., Patel, B., Eberwine, J., & Greenough, W. T.
Affiliations: University of Illinois Urbana-Champaign (US)
ORCID: Irwin, Scott A.
Klintsova, Anna Y.
Spencer, Corinne M.
Eberwine, James
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 1997-05-13
Volume: 94
Issue: 10
Pages: 5395-5400
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.94.10.5395
PMC: PMC24689
OpenAlex: W2002760096
Cited by: 644
References: 58
Citations by year: 2026: 2 · 2025: 8 · 2024: 8 · 2023: 11 · 2022: 11 · 2021: 12 · 2020: 8 · 2019: 14 · 2018: 13 · 2017: 19 · 2016: 15 · 2015: 23 · 2014: 24 · 2013: 27 · 2012: 29
FWCI: 12.99
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: FRAXA Research Foundation (MH35321)
John D. and Catherine T. MacArthur Foundation
National Institutes of Health
U.S. Public Health Service
National Institute on Aging (AG10154, R01AG010154)
National Institute of Mental Health (MH-35321, R01MH035321, R37MH035321)
National Center for Research Resources (RR 04050, P41RR004050)
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 and protein synthesis mechanisms
Keywords: FMRP, local protein synthesis, metabotropic glutamate receptor 1, polysomes, synaptoneurosomes, dendritic mRNA, synapse maturation, synaptic plasticity, dendritic translation
MeSH terms: Amino Acid Sequence, Animals, Antibodies, Brain, Dendrites, Glycine, Humans, Kinetics, Molecular Sequence Data, Nerve Tissue Proteins, Neurons, Organ Specificity, Polyribosomes, Resorcinols, RNA, Messenger, Synapses, Protein Biosynthesis, Oligonucleotide Probes, Gene Library, Antisense Elements (Genetics), RNA-Binding Proteins, Sequence Homology, Amino Acid, DNA, Complementary, Receptors, Metabotropic Glutamate, Neurotransmitter Agents, Excitatory Amino Acid Antagonists, Rats, Fragile X Mental Retardation Protein, Fragile X Messenger Ribonucleoprotein 1

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Fragile X mental retardation protein is translated near synapses in response to neurotransmitter activation

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