Fragile X Syndrome: Loss of Local mRNA Regulation Alters Synaptic Development and Function
Open accessAbstract
Fragile X syndrome is the most common inherited form of cognitive deficiency in humans and perhaps the best-understood single cause of autism. A trinucleotide repeat expansion, inactivating the X-linked FMR1 gene, leads to the absence of the fragile X mental retardation protein. FMRP is a selective RNA-binding protein that regulates the local translation of a subset of mRNAs at synapses in response to activation of Gp1 metabotropic glutamate receptors (mGluRs) and possibly other receptors. In the absence of FMRP, excess and dysregulated mRNA translation leads to altered synaptic function and loss of protein synthesis-dependent plasticity. Recent evidence indicates the role of FMRP in regulated mRNA transport in dendrites. New studies also suggest a possible local function of FMRP in axons that may be important for guidance, synaptic development, and formation of neural circuits. The understanding of FMRP function at synapses has led to rationale therapeutic approaches.
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The Fmr1 knockout mouse model lacks FMRP and recapitulates the main FXS phenotype, including deficiency in learning and memory, social behavior, and sensory processing.
“The mouse model of FXS, the Fmr1 knockout (KO) mice, lacks FMRP and recapitulates the main phenotype, including deficiency in learning and memory, social behavior, and sensory processing (Bassell and Warren, 2008; Liu and Smith, 2009).”
From Astrocytes in fragile X syndrome (2024) · cites this paper as Bassell and Warren, 2008
The ‘Fragile X Phenotype Suggests FMRP Affects Dendritic mRNA function’ section (page unavailable) identifies Fmr1 KO mice as an FXS model and reports altered learning and behavior. The axonal-development section reports altered sensory-related plasticity and pain processing in these mice. Our copy does not specifically establish deficits in social behavior or memory, so the full list of deficiencies is not supported. (LLM, conf=0.84)
Experimental — accuracy not yet measuredFMRP regulates dendritic targeting of mRNAs and controls protein synthesis and mRNA decay in neuronal soma and at synapses.
“FXS is due to loss of function of the RNA-binding protein FMRP (Bagni et al., 2012, Bassell and Warren, 2008), which regulates dendritic targeting of mRNAs (Dictenberg et al., 2008) and controls protein synthesis and mRNA decay in neuronal soma and at synapses (Bassell and Warren, 2008).”
From CYFIP1 Coordinates mRNA Translation and Cytoskeleton Remodeling to Ensure Proper Dendritic Spine Formation (2013) · cites this paper as Bassell and Warren, 2008
The review’s section on local translation reports dysregulated protein synthesis at FMRP-deficient synapses, and its section on regulated mRNA transport describes FMRP as required for activity-induced trafficking of some dendritic mRNAs. But the section on dendritic mRNA function describes a possible, cell-type-specific role in mRNA stability; it does not establish that FMRP controls mRNA decay in both neuronal somata and synapses. The citing sentence attaches a separate citation to dendritic targeting. (LLM, conf=0.86)
Experimental — accuracy not yet measuredFragile X syndrome is due to loss of function of the RNA-binding protein FMRP.
“FXS is due to loss of function of the RNA-binding protein FMRP (Bagni et al., 2012, Bassell and Warren, 2008), which regulates dendritic targeting of mRNAs (Dictenberg et al., 2008) and controls protein synthesis and mRNA decay in neuronal soma and at synapses (Bassell and Warren, 2008).”
From CYFIP1 Coordinates mRNA Translation and Cytoskeleton Remodeling to Ensure Proper Dendritic Spine Formation (2013) · cites this paper as Bassell and Warren, 2008
FMRP is an RNA-binding protein that regulates target RNAs post-transcriptionally and binds about 4% of brain mRNA.
“FMRP, translated from the Fragile X mental retardation-1 (FMR1) gene, is an RNA-binding protein involved in post-transcriptional regulation of target RNAs [157] and binds approximately 4% of the mRNA expressed in the brain [158].”
From Consensus Paper: Pathological Role of the Cerebellum in Autism (2012) · cites this paper as [158]
Fragile X syndrome is usually due to a trinucleotide expansion in FMR1 that results in transcriptional silencing of FMRP expression.
“Fragile X syndrome (FXS), the most common inherited cause of mental retardation (Bagni and Greenough, 2005; Bassell and Warren, 2008), is usually due to a trinucleotide expansion in the FMR1 gene that results in transcriptional silencing of FMRP (Fragile X mental retardation protein) expression.”
From Regulation of Synaptic Structure and Function by FMRP-Associated MicroRNAs miR-125b and miR-132 (2010) · cites this paper as Bassell and Warren, 2008
FMRP contains multiple RNA-binding domains and is widely thought to function as a translational suppressor of specific mRNAs, including MAP1b, CaMKIIα, and Arc.
“FMRP contains multiple RNA-binding domains and is widely thought to function as a translational suppressor of specific mRNAs, including MAP1b, CaMKIIα, and Arc (Bassell and Warren, 2008).”
From Regulation of Synaptic Structure and Function by FMRP-Associated MicroRNAs miR-125b and miR-132 (2010) · cites this paper as Bassell and Warren, 2008
FMR1 KO usually has subtle or no overt effects on expression of established FMRP target genes.
“given that FMR1 KO usually has subtle or no overt effects even on expression of “established” FMRP target genes (Bassell and Warren, 2008; Darnell et al., 2005b; Muddashetty et al., 2007).”
From Regulation of Synaptic Structure and Function by FMRP-Associated MicroRNAs miR-125b and miR-132 (2010) · cites this paper as Bassell and Warren, 2008
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References 120 · Cited by 1,051
- Authors
- Bassell, G. J., & Warren, S. T.
- Affiliations
- Emory University (US)
- Corresponding author
- Bassell, Gary J.
- Warren, Stephen T.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2008-10
- Volume
- 60
- Issue
- 2
- Pages
- 201-214
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC3691995
- OpenAlex
- W2054091111
- Cited by
- 1,051
- References
- 120
- Citations by year
- 2026: 25 · 2025: 25 · 2024: 39 · 2023: 38 · 2022: 47 · 2021: 35 · 2020: 53 · 2019: 53 · 2018: 45 · 2017: 53 · 2016: 51 · 2015: 63 · 2014: 85 · 2013: 89 · 2012: 111
- FWCI
- 7.39
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1786 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship@UMassChan (submittedVersion)
- Funders
- Simons Foundation (NS051127)
- 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, FMR1 gene, trinucleotide repeat expansion, metabotropic glutamate receptors, dendritic mRNA transport, synaptic plasticity, autism spectrum disorder, cognitive disability, neural circuit formation
- MeSH terms
- Animals, Biological Transport, Active, Brain, Fragile X Syndrome, Humans, Synaptic Transmission, Neuronal Plasticity, RNA, Messenger, Neurites, Receptors, Metabotropic Glutamate, Fragile X Mental Retardation Protein, Fragile X Messenger Ribonucleoprotein 1
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