The DOI matches its Crossref record; 102 of the 102 references it cites were found in a registry or an index; none of the 43 sources its claims cite is checked for support yet.
FMRP Stalls Ribosomal Translocation on mRNAs Linked to Synaptic Function and Autism
Open accessAbstract
Summary FMRP loss-of-function causes Fragile X Syndrome (FXS) and autistic features. FMRP is a polyribosome-associated neuronal RNA-binding protein, suggesting that it plays a key role in regulating neuronal translation, but there has been little consensus regarding either its RNA targets or mechanism of action. Here we use high throughput sequencing of RNAs isolated by crosslinking immunoprecipitation (HITS-CLIP) to identify FMRP interactions with mouse brain polyribosomal mRNAs. FMRP interacts with the coding region of transcripts encoding pre- and postsynaptic proteins, and transcripts implicated in autism spectrum disorders (ASD). We developed a brain polyribosome-programmed translation system, revealing that FMRP reversibly stalls ribosomes specifically on its target mRNAs. Our results indicate that loss of a translational brake on the synthesis of a subset of synaptic proteins may contribute to FXS. In addition, they provide insight into the molecular basis of the cognitive and allied defects in FXS and ASD, and suggest multiple targets for clinical intervention.
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“our data conservatively identified 661 novel FMRP mRNA targets not found previously.”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Results > Identity and functions encoded by FMRP target transcripts
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“comparison with 83 targets obtained using the APRA method (Miyashiro et al., 2003) revealed only 6 in common (p=0.28; Tables S2C and S3A).”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Results > Identity and functions encoded by FMRP target transcripts
What the sources say
- Not checked yetcites Miyashiro et al., 2003 source
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“In both analyses, proteins encoded by FMRP-bound transcripts were enriched in those related to neuronal and synaptic transmission and regulation of small GTPase mediated signaling.”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Results > Identity and functions encoded by FMRP target transcripts
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“Importantly, the number of FMRP tags per transcript showed little correlation with transcript abundance or length (Figure S1E–F).”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Results > FMRP RNA targets in mouse brain polyribosomes
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In the paper
“The results were very reproducible, with high correlations seen between exonic tag number per gene in CLIP experiments using different anti-FMRP antibodies, purification protocols and sequencing platforms (Figure S1A–B).”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Results > FMRP RNA targets in mouse brain polyribosomes
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In the paper
“We developed a brain polyribosome-programmed translation system, revealing that FMRP reversibly stalls ribosomes specifically on its target mRNAs.”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Abstract
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In the paper
“FMRP interacts with the coding region of transcripts encoding pre- and postsynaptic proteins, and transcripts implicated in autism spectrum disorders (ASD).”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Abstract
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In the paper
“We identified a stringent set of 842 FMRP target transcripts (FDR <0.01) (Tables S2A–S2C).”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Results > Identity and functions encoded by FMRP target transcripts
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In the paper
“The results were specific, as little correlation was seen between FMRP mRNA targets and either Hu targets or those of another neuronal RNABP, Nova (Figure S1C–D).”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Results > FMRP RNA targets in mouse brain polyribosomes
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“Consistent with this interpretation, we found that the ultrastructure of the polyribosomal complexes in the MN-treated fractions was indistinguishable from those in untreated fractions (Figure 7G vs. 7A).”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Results > Characterization of the FMRP-stalled complex
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“54% of RIP-CHIP targets (p=2.4 × 10−121; Tables S2C and S3A) were present in the FMRP CLIP target list, accounting for 24% of CLIP targets.”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Results > Identity and functions encoded by FMRP target transcripts
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In the paper
“These FMRP targets were detectable with both antibodies (100%), using both CLIP protocols (100%), different sequencing platforms (100%), and were biologically reproducible (99% were detectable in at least 6 out of 7 experiments).”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Results > Identity and functions encoded by FMRP target transcripts
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In the paper
“Significantly, addition of kcRNA after run-off did not cause a shift in the distribution of mRNAs, ruling out the possibility that observed changes in mRNA distributions were due to the loss of the mass of FXRPs alone (Figure S4C).”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Results > Loss of FMRP function relieves ribosome stalling
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“The labeling of these complexes was dependent on FMRP, relative to an overexpressed negative control (EGFP alone; Figure S7B), demonstrating the physical association of FMRP with stalled polyribosomes in vivo (Figure 7C).”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Results > Characterization of the FMRP-stalled complex
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“Strikingly, a significant fraction of the mGluR5 (62%, p=5.8 × 10−22; Tables S3A and S3D) and NMDAR (34%, p=7.4 × 10−23; Tables S3A and S3E) receptor complex proteins were FMRP targets.”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Results > Identity and functions encoded by FMRP target transcripts
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In the paper
“In contrast, PABP or Hu shifted to lighter fractions, as did FMRP when EDTA was added to dissociate ribosomes (Figure 3C).”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Results > Loss of FMRP function relieves ribosome stalling
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“In two biological replicate CLIP experiments, we found that FMRP was crosslinked to the same target transcripts (Figure 7I; Table S7) and with the same CDS distribution in puromycin-insensitive (stalled) and steady-state complexes (Figure 7J).”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Results > Characterization of the FMRP-stalled complex
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In the paper
“Incubation of sucrose-gradient purified polyribosomes with MN, followed by separation of ribosomes from released material on a sucrose cushion, revealed that the majority of FMRP pelleted with the ribosomes (Figure 7D–E). As controls, PABP (bound to mRNA poly(A) tails) was readily released from polyribosomes by MN, while rpP0 was MN resistant.”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Results > Characterization of the FMRP-stalled complex
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In the paper
“We observed some correlation between coding sequence (CDS) length and RRS among all transcripts (R2=0.41); this was largely due to FMRP targets (Figure 6E, R2=0.56 for targets; R2=0.17 for non-targets), consistent with FMRP stalling ribosomes across the length of the CDS of its target transcripts.”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Results > Loss of FMRP function relieves ribosome stalling
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In the paper
“it is likely to be dynamic, as it can be acutely reversed by RNA decoys in run-off assays.”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Discussion
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“Restricting our analysis to loci containing 5 or fewer protein-coding genes, we found a significant number (25/196) of candidate autism susceptibility genes in duplicated loci are FMRP targets (Tables S3A and S5, p=0.001).”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Results > Overlap of FXS and autism spectrum disorders (ASDs)
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- Rests on an assumption: The SFARI autism candidate gene list provides a valid set of ASD susceptibility genes.
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In the paper
“No loss of polyribosome integrity was observed in parallel reactions incubated with cycloheximide (CHX) at 30°C for up to 45 minutes, indicating that ribosome run-off could not be explained by nuclease activity.”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Results > Loss of FMRP function relieves ribosome stalling
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In the paper
“This run-off was accompanied by 35S-methionine incorporation in a time- and brain polyribosome-dependent manner that was not increased if hippuristanol was omitted (Figure S3B–C), indicating that elongation can occur on pre-existing brain polyribosome-associated mRNAs in the absence of initiation in the IVTEBP system.”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Results > Loss of FMRP function relieves ribosome stalling
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In the paper
“Strikingly, 66% of FMRP mRNA binding was within the coding sequence (CDS), with no specific position relative to the start and stop codons, and with lower tag density in the 3′ or 5′ UTRs; in comparison, RNA tags of the neuronal Hu proteins mapped predominantly to the 3′ UTR of target transcripts (Figure 2C).”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Results > FMRP binds coding sequences and stalls ribosomes
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In the paper
“We found a small but significant increase in protein synthesis of both FMRP targets in the absence of functional FMRP, similar to results reported for Camk2a by Bear and colleagues in slice cultures (Osterweil et al., 2010), with no significant change in either overall protein synthesis or in the synthesis of the non-target PABP (Figure 6G and Figure S6).”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Results > Loss of FMRP function relieves ribosome stalling
What the sources say
- Not checked yetcites Osterweil et al., 2010 source
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In the paper
“The RRS was not dependent on transcript abundance (R2=0.01), nor how many ribosomes were associated with the transcript in the steady state (R2=0.07).”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Results > Loss of FMRP function relieves ribosome stalling
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In the paper
“in the presence of puromycin at 30°C, ribosomal run-off was evident within 2 minutes, reached a plateau by 15 minutes, and was saturable, as neither a ten-fold increase in puromycin nor incubation for up to 45 minutes caused additional run-off.”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Results > Loss of FMRP function relieves ribosome stalling
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In the paper
“FMRP co-IP’d with rpP0-containing complexes, as did the ribosomal proteins rpL5 and rpS6 (Figure 7H), demonstrating a direct association of FMRP with ribosome-containing complexes, reminiscent of previous findings in cultured cells (Khandjian et al., 1996; Siomi et al., 1996).”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Results > Characterization of the FMRP-stalled complex
What the sources say
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In the paper
“FMRP also targets ERK1 and the mTOR inhibitors Pten, Nf1 and Tsc2”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Discussion
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In the paper
“Rai1 and Ube3a, harbored FMRP CLIP tags in 6/7 and 3/7 experiments, respectively”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Discussion
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In the paper
“We find that FMRP targets fall into several functional categories, as do ASD candidate genes (Sebat et al., 2007; Pinto et al., 2010) and the overlap is enriched in several inter-related functional categories, including synaptic cell adhesion molecules, the NMDAR complex, the mTOR pathway, and regulators of the small GTPases.”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Discussion
What the sources say
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In the paper
“mGluR5 and the NMDAR subunits, the only glutamate receptors known to mediate protein-synthesis dependent long-term synaptic plasticity, are themselves FMRP targets, as are many other protein components of their macromolecular complexes at the synapse.”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Discussion
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In the paper
“FMRP loss-of-function causes Fragile X Syndrome (FXS) and autistic features.”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Abstract
What the sources say
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In the paper
“FMRP is a polyribosome-associated neuronal RNA-binding protein, suggesting that it plays a key role in regulating neuronal translation, but there has been little consensus regarding either its RNA targets or mechanism of action.”
- Also stated in: § Introduction · plain
“the majority of FMRP is associated with polyribosomes (Feng et al., 1997b; Khandjian et al., 2004; Stefani et al., 2004).”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Abstract
What the sources say
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- Also stated in: § Introduction · plain
In the paper
“we first took advantage of the observation that 85–90% of FMRP is associated with polyribosomes in the brain (Figure 1B–D) as a purification step (Stefani et al., 2004).”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Results > FMRP RNA targets in mouse brain polyribosomes
What the sources say
- Not checked yetcites Stefani et al., 2004 source
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In the paper
“a missense mutation in the second RNA binding domain (I304N) abolishes FMRP polyribosome association (Zang et al., 2009; Feng et al., 1997a) and causes a Fragile X phenotype in mice (Zang et al., 2009) and humans (DeBoulle et al., 1993).”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Introduction
What the sources say
- Not checked yetcites Zang et al., 2009 source
- Not checked yetcites Feng et al., 1997a
- Not checked yetcites DeBoulle et al., 1993
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In the paper
“In the brain, FMRP is present in the neuronal cell body, proximal dendrites and axons (Christie et al., 2009)”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Introduction
What the sources say
- Not checked yetcites Christie et al., 2009 source
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In the paper
“The net result is that they have met with limited success either in deriving a consensus set of FMRP mRNA targets, in identifying mRNAs that can be validated as targets in genetic systems, or in defining FMRP function.”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Introduction
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In the paper
“FMRP binds to RNA in vitro (Siomi et al., 1993) with high affinity for kissing complex and G-quadruplex motifs mediated through its KH and RGG-type RNA binding domains, respectively (Darnell et al., 2005a; Darnell et al., 2001).”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Introduction
What the sources say
- Not checked yetcites Siomi et al., 1993
- Not checked yetcites Darnell et al., 2005a
- Not checked yetcites Darnell et al., 2001 source
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In the paper
“suggesting that ribosomes are stalled on FMRP-bound mRNAs in an FMRP-dependent manner in vivo, with stalling relieved in mice harboring either of two different FMRP loss-of function mutations.”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Results > Loss of FMRP function relieves ribosome stalling
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- Rests on an assumption: The Fmr1 knockout and I304N mouse models faithfully represent the translational consequences of FMRP loss in human FXS.
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In the paper
“Thus FMRP appears to associate with the CDS of transcripts on which some of the ribosomes may be stalled, suggesting that FMRP might play a role in regulating translation at the level of elongation.”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Results > FMRP binds coding sequences and stalls ribosomes
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In the paper
“Stalled ribosomes may also protect mRNA from degradation during transport or storage.”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Discussion
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In the paper
“It is increasingly recognized that a large fraction of cellular mRNA may be translated within subcellular domains (Martin and Ephrussi, 2009)”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Discussion
What the sources say
- Not checked yetcites Martin and Ephrussi, 2009
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In the paper
“FXS is the leading monogenic cause of ASDs, accounting for up to 5% of all cases (Kelleher and Bear, 2008), and 90% of affected males show autistic behaviors (Hernandez et al., 2009).”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Results > Overlap of FXS and autism spectrum disorders (ASDs)
What the sources say
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
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In the paper
“Therefore FMRP-mediated ribosomal stalling can be functional and dynamic, as acutely relieving it leads to increased synthesis of new protein.”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Results > Loss of FMRP function relieves ribosome stalling
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In the paper
“The stalling of a single ribosome almost immediately slows protein production, while recycled ribosomes continue to re-initiate and restore the “loaded” state (Figure 7C) (Wolin and Walter, 1988).”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Discussion
What the sources say
- Not checked yetcites Wolin and Walter, 1988
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In the paper
“These observations suggest that FMRP may play a role in homeostatic synaptic plasticity (Turrigiano, 2008). In this model, FMRP would act to repress the translation stimulated by neuronal activity to generate a feedback loop limiting neuronal responses to activity at the level of the neuron rather than a specific synapse.”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Discussion
What the sources say
- Not checked yetcites Turrigiano, 2008 source
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In the paper
“Taken together, these results demonstrate that acute loss of polyribosome-associated FMRP yields the same relief of translational repression as long-term loss of function in mouse models, indicating that ribosome stalling is likely to be caused directly and reversibly by FMRP.”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Results > Loss of FMRP function relieves ribosome stalling
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: The Fmr1 knockout and I304N mouse models faithfully represent the translational consequences of FMRP loss in human FXS.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Experiments gave reproducible results in 4/4, 2/2 and one biologic replicate with kcRNA decoy, I304N mice, and KO mice, respectively. In sum, these results were consistent in 7/7 experiments using three loss of function models.”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Experimental Procedures
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may state two separate claims as one.
In the paper
“The effects of FMRP were measured using three loss-of-function models including the Fmr1 KO and I304N point mutant knock-in mice, and where indicated, addition of in vitro transcribed kcRNA (Darnell et al., 2005a) as a competitive RNA ligand (decoy)”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Experimental Procedures
What the sources say
- Not checked yetcites Darnell et al., 2005a
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“experimental results were reproduced in multiple independent experiments as noted throughout.”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Experimental Procedures
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Mice used as experimental controls were littermates”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Experimental Procedures
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“FMRP targets were ranked using a nonparametric method that considered both the total number of tags/gene in seven different CLIP experiments and experimental reproducibility.”
§ FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism > Experimental Procedures
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
The paper relies on this without support.
The Fmr1 knockout and I304N mouse models faithfully represent the translational consequences of FMRP loss in human FXS.
“Studies of Fmr1 knockout (KO) and I304N mice have documented a number of defects in synaptic plasticity (Pfeiffer and Huber, 2009; Zang et al., 2009).”
The paper relies on this without support.
The SFARI autism candidate gene list provides a valid set of ASD susceptibility genes.
“Comparison of the 842 FMRP target genes with 117 evaluable candidate genes from the SFARI database of autism candidate genes (http://gene.sfari.org (Basu et al., 2009)) revealed a highly significant overlap with 28 FMRP targets (24%, p=1.0 × 10−8; Table S3A), including several well-studied autism candidate genes such NLGN3, NRXN1, SHANK3, PTEN, TSC2, and NF1 (Table S5).”
The paper relies on this without support.
The P8-P25 mouse brain developmental window is relevant to human FXS.
“our results clearly demonstrate that on a cell population level there is no FMRP-dependent difference in steady state mRNA polysome distribution in the P8-P25 mouse brain.”
The paper relies on this without support.
Learning and memory depend on changes in long-term synaptic strength and on new protein synthesis.
“Learning and memory almost certainly involve changes in long-term synaptic strength and require new protein synthesis.”
The paper relies on this without support.
The molecular basis of symptom overlap between Fragile X Syndrome and autism is not well understood.
“The molecular basis for the overlap in symptoms between Fragile X Syndrome and autism is poorly understood.”
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Indeed, in the mouse brain, Cyfip2 mRNA (but not Cyfip1 mRNA) was reported to be a target of FMRP that represses its translation (Darnell et al., 2011).”
From New insights into the regulatory function of CYFIP1 in the context of WAVE- and FMRP-containing complexes (2017) · cites this paper as Darnell et al., 2011
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“In particular, in Mnk1-null neurons, altered expression of a subset of proteins was observed, including 26 proteins whose encoding mRNAs are bound by FMRP in translating ribosomes (Genheden et al., 2016; Darnell et al., 2011).”
From New insights into the regulatory function of CYFIP1 in the context of WAVE- and FMRP-containing complexes (2017) · cites this paper as Darnell et al., 2011
The cited source says what the claim attributes to it.
In the citing paper
“FMRP acts as an overall suppressor of protein synthesis (Laggerbauer et al., 2001), a function which it achieves by regulating nuclear-cytoplasmic translocation (Feng et al., 1997; Kim et al., 2009) and translation of various mRNAs. Many of these RNAs are associated with synapse function (Darnell et al., 2011).”
From Astrocytes in fragile X syndrome (2024) · cites this paper as Darnell et al., 2011
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“It is interesting to notice that in mouse, while we are describing CYFIP1 as an antagonist of FMRP, CYFIP2 has been described both as a co-effector (e.g. depletion of CYFIP2 worsens some phenotypes of Fmr1-knockout mouse) (Han et al., 2015) and a downstream target of FMRP.”
From New insights into the regulatory function of CYFIP1 in the context of WAVE- and FMRP-containing complexes (2017) · cites this paper as Darnell et al., 2011
Experimental — accuracy not yet measuredIn the citing paper
“mRNA translation of BRSK2, ITSN1, and RALGAPB in neurons is predicted to be regulated by FMR1 protein.35”
From Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes (2019) · cites this paper as [35]
In the citing paper
“Encoded by the FMR1 gene, Fragile X mental retardation protein (FMRP) mostly operates as an mRNA-binding protein (Fig. 5B2) that represses translation of an emerging subset of mRNAs (Brown et al., 2001; Darnell et al., 2001; Darnell et al., 2011; Santoro et al., 2012), among other functions (Contractor et al., 2015).”
From Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops (2016) · cites this paper as Darnell et al., 2011
In the citing paper
“This in turn will increase the abundance of regulatory proteins such as Arc, CaMKIIα, PSD95, and CaMKIIβ (Darnell et al., 2011; Muddashetty et al., 2011; Niere et al., 2012; Park et al., 2008; Stefanovic et al., 2015), setting up the spine for a binary decision, to undergo LTD or LTP.”
From Unifying Views of Autism Spectrum Disorders: A Consideration of Autoregulatory Feedback Loops (2016) · cites this paper as Darnell et al., 2011
In the citing paper
“FMRP has recently been reported to modulate the rate of translational elongation of mRNAs that encode synaptic proteins33, suggesting that the decrease in FMRP expression that occurs in Fragile X syndrome may result in the dysregulation of synaptic protein expression owing to an impairment in translational control23.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [33]
In the citing paper
“This suggests that these ASD candidate genes and FMRP may function in overlapping pathways.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [33]
In the citing paper
“Many other FMRP targets have been shown to be involved in synaptic plasticity, and there is significant overlap between FMRP targets and ASD candidate genes, including NLGN3, NRXN1, SHANK3, PTEN, TSC1 and NF123,33.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [33]
In the citing paper
“FMRP may act as one component of a central regulator of synaptic plasticity, among others such as TSC2 (Darnell et al., 2011; Auerbach et al., 2011).”
From De Novo Gene Disruptions in Children on the Autistic Spectrum (2012) · cites this paper as Darnell et al., 2011
In the citing paper
“A set of 842 FMRP-associated genes has been enumerated by cross-linking, immunoprecipitation, and high-throughput sequencing (HITS-CLIP), and this set was previously noted to overlap candidate genes from de novo CNVs (Darnell et al., 2011).”
From De Novo Gene Disruptions in Children on the Autistic Spectrum (2012) · cites this paper as Darnell et al., 2011
In the citing paper
“RNA targets of both FMRP (Darnell et al., 2011) and CELF4 (Wagnon et al., 2012) were reported to be significantly enriched for ASD genes, and ASD candidate genes were further enriched among the common targets of FMRP and CELF4 (Wagnon et al., 2012).”
From Getting to the cores of autism (2019) · cites this paper as Darnell et al., 2011
In the citing paper
“A seminal example is the Fragile X mental retardation protein (FMRP) (Darnell et al., 2011), and other RBPs that are associated with ASD include CELF4 (Wagnon et al., 2012), ELAVL3 (Ince-Dunn et al., 2012) and GIGYF1 (Peter et al., 2017).”
From Getting to the cores of autism (2019) · cites this paper as Darnell et al., 2011
In the citing paper
“These authors reported that many of the protein-interacting partners of FMRP harbour ASD-associated common variants35.”
From Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism (2014) · cites this paper as [35]
In the citing paper
“Direct evidence for the role of Fragile X mental retardation protein (FMRP) in autism has been provided by Darnell et al.”
From Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism (2014) · cites this paper as [35]
In the citing paper
“FMRP and its interacting partners (FMRP interacting) implicated with translational regulation of synaptic proteins35 and shown to be enriched with diverse class of ASD variants57.”
From Transcriptome analysis reveals dysregulation of innate immune response genes and neuronal activity-dependent genes in autism (2014) · cites this paper as [35]
In the citing paper
“Using CLIP–seq, investigators identified the RNA binding targets of the translational regulator fragile X mental retardation protein (FMRP)116, and a subsequent analysis found that these targets are highly enriched for de novo mutations in ASD72.”
From Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders (2015) · cites this paper as [116]
In the citing paper
“This study identified a stringent set of 842 FMRP target transcripts, many of them associated with neuropsychiatric disorders.”
From Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome (2018) · cites this paper as [15]
In the citing paper
“This highlights the fact that FMRP has broad regulatory roles at the synapse.”
From Drug development for neurodevelopmental disorders: lessons learned from fragile X syndrome (2018) · cites this paper as [15]
In the citing paper
“We also find significant enrichment of splicing changes in targets of two RNA binding proteins that regulate synaptic transmission and whose targets are implicated in both ASD and SCZ, the neuronal splicing regulator RBFOX1 (FDR=5.16×10−11) (32) and the fragile X mental retardation protein (FMRP) (FDR=3.10×10−21) (33).”
From Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder (2018) · cites this paper as [33]
In the citing paper
“A strong and consistent finding in exome-sequencing studies of schizophrenia involves an excess of variants in genes whose mRNAs are bound by the fragile X mental retardation protein (FMRP)9,12,27.”
From Increased burden of ultra-rare protein-altering variants among 4,877 individuals with schizophrenia (2016) · cites this paper as [27]
In the citing paper
“Across two FMRP target sets72, 73 (see Supplementary Table S1 for gene lists) we found that MIA-downregulated genes are highly enriched in FMRP targets (Darnell targets: OR=7.81, P=2.56e-127; Ascano targets: OR=2.07, P=1.75e-30).”
From Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder (2018) · cites this paper as [73]
In the citing paper
“FMRP is an RNA-binding protein known to interact with specific mRNAs in the brain and regulate synaptic plasticity-dependent local protein synthesis [18, 80, 275].”
From Autism spectrum disorder: neuropathology and animal models (2017) · cites this paper as [80]
In the citing paper
“FMRP regulates stability, subcellular transport, and translation of neuronal mRNAs encoding for proteins involved the in synaptic structure and function (58,(65)(66)(67).”
From Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics (2012) · cites this paper as [58]
In the citing paper
“Recent evidence indicates that dysregulation and or mutations of FMRP-interacting proteins, such as the cytoplasmic FMRP-interacting protein 1 (CYFIP1) (52-55), eukaryotic initiation factor 4 (eIF4E) (56,57), and a subset of FMRP mRNA targets (58), may contribute to the ASD phenotype observed in FXS.”
From Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics (2012) · cites this paper as [58]
In the citing paper
“FMRP, the protein product of FMR1, regulates roughly 20% of ASD susceptibility genes (Darnell et al., 2011; Driesche et al., 2019)”
From Parallel social information processing circuits are differentially impacted in autism (2020) · cites this paper as Darnell et al., 2011
Citations
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Metadata
- Authors
- 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., Licatalosi, D. D., Richter, J. D., & Darnell, R. B.
- Affiliations
- Rockefeller University (US)
- University of Massachusetts Chan Medical School (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Darnell, Jennifer C.
- Darnell, Robert B.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2011-07
- Volume
- 146
- Issue
- 2
- Pages
- 247-261
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3232425
- OpenAlex
- W2052326665
- Semantic Scholar
- 938ef69c910e44431f6c9295bcd1a3a11aa04807
- Cited by
- 2,072
- References
- 102
- Citations by year
- 2026: 78 · 2025: 100 · 2024: 127 · 2023: 118 · 2022: 136 · 2021: 148 · 2020: 182 · 2019: 159 · 2018: 168 · 2017: 159 · 2016: 151 · 2015: 144 · 2014: 158 · 2013: 125 · 2012: 97
- FWCI
- 79.81
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- Georgia Clinical and Translational Science Alliance
- National Institute on Aging (R01AG030323, AG30323)
- National Institute of General Medical Sciences (GM95713, K99GM095713, GM46779, R01GM046779)
- National Institute of Neurological Disorders and Stroke (R01NS040955, NS34389, NS40955)
- National Center for Research Resources (UL1RR024143)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD40647, R01HD040647, HD37267)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Keywords
- FMRP, fragile X syndrome, autism spectrum disorder, ribosome translocation, polysomes, synaptic proteins, RNA-binding proteins, HITS-CLIP, translational regulation
- MeSH terms
- Animals, Autistic Disorder, Brain, Fragile X Syndrome, Humans, Polyribosomes, Ribosomes, Synapses, Protein Biosynthesis, RNA-Binding Proteins, Sequence Analysis, RNA, Mice, Knockout, Mice, Fragile X Mental Retardation Protein, Fragile X Messenger Ribonucleoprotein 1
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