CYFIP1 Coordinates mRNA Translation and Cytoskeleton Remodeling to Ensure Proper Dendritic Spine Formation

Probably not a substantial claim: may not pass S3 (load-bearing).

These disorders are synaptopathies in which dysgenesis of dendritic spines is a recurrent anatomical feature.

“These disorders are synaptopathies (Ehninger and Silva, 2009) in which dysgenesis of dendritic spines is a recurrent anatomical feature (Penzes et al., 2011).”

• cites Penzes et al., 2011 sourceSupported

May combine two claims.

The predicted conformational change moves the domain carrying the eIF4E-binding site toward the outside, allowing Lys743 to interact with Glu132 of eIF4E.

“The consequence of this conformational change is that the domain carrying the eIF4E-binding site moves toward the outside (Figure 2D), allowing Lys743 to interact with Glu132 of eIF4E (Figure 1A) (Napoli et al., 2008).”

• cites Napoli et al., 2008 sourcePartly supported

  The Figure 2 discussion (p. 4) predicts that CYFIP1 Lys743 is positioned to form a salt bridge with Glu132 of eIF4E. It describes a predicted shape of the binding peptide, but not a conformational change that moves the eIF4E-binding domain outward; that part of the attributed claim is unsupported. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

Upon activation of BDNF/TrkB or group I metabotropic glutamate receptors, CYFIP1 is released from eIF4E and translation ensues.

“Upon activation of the brain-derived neurotrophic factor (BDNF)/NT-3 growth factor receptor (TrkB) or group I metabotropic glutamate receptors (mGluRs), CYFIP1 is released from eIF4E and translation ensues (Napoli et al., 2008).”

• cites Napoli et al., 2008 sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

The CYFIP1/SRA1 gene is located in a chromosomal region linked to various neurological disorders, including intellectual disability, autism, and schizophrenia.

“The CYFIP1/SRA1 gene is located in a chromosomal region linked to various neurological disorders, including intellectual disability, autism, and schizophrenia.”

• cites Tam et al., 2010 sourceNot checked — no full text of the source
• cites Zhao et al., 2012 sourceSupported

Classified as probably not a substantial claim.

Fragile 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).”

• cites Bagni et al., 2012 sourceSupported
• cites Bassell and Warren, 2008 sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

ARC is required for mGluR-LTD and AMPAR internalization.

“ARC is required for mGluR-LTD and AMPAR internalization (Waung et al., 2008)”

• cites Waung et al., 2008 sourceSupported

May combine two claims.

In the WRC crystal structure, NCKAP1 interacts with CYFIP1 over a large surface, and Lys743, critical for eIF4E binding, is covered by NCKAP1 and not accessible to solvent when CYFIP1 is in the WRC.

“According to the crystal structure of the WRC that includes CYFIP1 (Chen et al., 2010), NCKAP1 interacts with CYFIP1 over a large surface (Figure 1A, upper panel); the lysine critical for the binding to eIF4E (Lys743) (Napoli et al., 2008) is covered by NCKAP1 and therefore is not accessible to solvent when CYFIP1 is in the WRC (Figure 1A, bottom panels, Table S1).”

• cites Chen et al., 2010 sourcePartly supported

  The Overall structure of the WRC section says Sra1/CYFIP1 and Nap1/NCKAP1 interact extensively. The Discussion says the proposed mode of eIF4E binding is incompatible with the WRC structure. Our copy does not identify Lys743 or state that NCKAP1 covers that residue and makes it inaccessible to solvent. (LLM, conf=0.84)

  Experimental — accuracy not yet measured
• cites Napoli et al., 2008 sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

Rac1 signaling can activate the WRC through CYFIP1.

“In particular, the Rac1 signaling can activate the WRC through CYFIP1 (Chen et al., 2010, Eden et al., 2002, Kobayashi et al., 1998, Schenck et al., 2003, Steffen et al., 2004).”

• cites Chen et al., 2010 sourceSupported
• cites Eden et al., 2002 sourceNot checked — no full text of the source
• cites Kobayashi et al., 1998 sourcePartly supported

  The Abstract reports that Sra-1 directly interacts with activated Rac1, and Results and Discussion links Sra-1 to Rac1-induced membrane ruffling. Our copy does not identify Sra-1 as CYFIP1 or describe activation of the WRC, so it supports the Rac1–Sra-1 connection but not the full mechanism claimed. (LLM, conf=0.88)

  Experimental — accuracy not yet measured

May combine two claims.

Effects of CYFIP1 reduction on dendritic spines are compatible with the enhanced mGluR-dependent LTD and behavioral abnormalities caused by Cyfip1 haploinsufficiency, similar to the phenotype observed in Fmr1 KO mice.

“Effects of CYFIP1 reduction on dendritic spines are compatible with the enhanced mGluR-dependent LTD and behavioral abnormalities caused by Cyfip1 haploinsufficiency (Bozdagi et al., 2012), similar to the phenotype observed in Fmr1 KO mice (Bear et al., 2004).”

• cites Bozdagi et al., 2012 sourceSupported
• cites Bear et al., 2004 sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

FMRP 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).”

• cites Dictenberg et al., 2008 sourceSupported
• cites Bassell and Warren, 2008 sourcePartly supported

  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 measured

Probably not a substantial claim: may not pass S3 (load-bearing).

Rac1 activation was shown to translocate CYFIP1 to actin-rich domains involved in cellular protrusions in mouse fibroblasts.

“Rac1 activation was shown to translocate CYFIP1 to actin-rich domains involved in cellular protrusions in mouse fibroblasts (Castets et al., 2005).”

• cites Castets et al., 2005 sourceSupported

May combine two claims.

The observed spine dysmorphogenesis is in line with defects in WRC components, loss of FMRP, overexpression of ARC, or Rac1 blockade during early development.

“the observed spine dysmorphogenesis is in line with defects in the WRC components (Grove et al., 2004, Kim et al., 2006, Soderling et al., 2007), loss of FMRP (Comery et al., 1997, Cruz-Martín et al., 2010, Galvez and Greenough, 2005, Irwin et al., 2002), overexpression of ARC (Peebles et al., 2010), or Rac1 blockade during early development (Tashiro and Yuste, 2004).”

• cites Grove et al., 2004 sourceSupported
• cites Kim et al., 2006 sourceNot checked — no full text of the source
• cites Soderling et al., 2007 sourceSupported

Probably not a substantial claim: may not pass S3 (load-bearing).

Dendritic spine maturation is critical for correct brain functioning.

“Dendritic spine maturation is critical for correct brain functioning (Penzes et al., 2011).”

• cites Penzes et al., 2011 sourceSupported

May combine two claims.

The segregation of CYFIP1 into the two complexes relies on alternative CYFIP1 conformations: a planar one needed for the WRC and a more globular one for interaction with eIF4E.

“The segregation into the two complexes relies on alternative CYFIP1 conformations, a planar one needed for the WRC (Chen et al., 2010), and a more globular one for the interaction with eIF4E.”

• cites Chen et al., 2010 sourcePartly supported

  The Overall structure of the WRC section describes Sra1/CYFIP1 as part of an elongated structural platform in the WRC. The Discussion suggests that Sra1 may partition between the WRC and a separate state that binds eIF4E, but it does not establish that segregation relies on alternative CYFIP1 conformations or that a planar conformation is required for the WRC. No page numbers are available in our copy. (LLM, conf=0.82)

  Experimental — accuracy not yet measured

May combine two claims.

CYFIP1 is implicated in intellectual disability, autism spectrum disorder, and schizophrenia.

“CYFIP1 is implicated in ID (Cooper et al., 2011, Napoli et al., 2008, Nowicki et al., 2007, Schenck et al., 2003), ASD (Cooper et al., 2011, Doornbos et al., 2009, Murthy et al., 2007, Nishimura et al., 2007, Sahoo et al., 2006, van der Zwaag et al., 2010, von der Lippe et al., 2010), and SCZ (Tam et al., 2010, Zhao et al., 2012).”

• cites Cooper et al., 2011 sourceCould not verify

  The Discussion reports pathogenicity of 15q11.2 deletions in affected individuals, and the Methods describe an ID/DD cohort that includes autism cases. But searches for CYFIP1 and its proposed links to ID and ASD found no passage identifying that gene or linking it to either condition. The citing sentence attributes schizophrenia to other sources, not Cooper et al. (LLM, conf=0.73)

  Experimental — accuracy not yet measured
• cites Napoli et al., 2008 sourceSupported
• cites Nowicki et al., 2007 sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

NCKAP1 and eIF4E have been shown to be genetically associated with autism spectrum disorder.

“the two key CYFIP1 interactors examined here, NCKAP1 and eIF4E, have been shown to be genetically associated with ASD (Iossifov et al., 2012, Neves-Pereira et al., 2009).”

• cites Iossifov et al., 2012 sourceCould not verify

  The Discussion’s “Candidate Genes” section (page not supplied) discusses ASD-linked mutations in other genes but does not identify NCKAP1 or eIF4E. Searches for NCKAP1, eIF4E, and their association with autism found no passage in our copy addressing the claimed associations. (LLM, conf=0.73)

  Experimental — accuracy not yet measured
• cites Neves-Pereira et al., 2009 sourceNot checked — no full text of the source

Probably not a substantial claim: may not pass S3 (load-bearing).

Spine dysmorphogenesis is a common feature of several neuropsychiatric disorders.

“Spine dysmorphogenesis is a common feature of several neuropsychiatric disorders (Penzes et al., 2011).”

• cites Penzes et al., 2011 sourceSupported

May combine two claims.

Cyfip1 knockdown robustly affects spine morphology: mature spines (stubby and mushroom) are significantly reduced, whereas elongated, immature-looking spines increase in number.

“However, Cyfip1 knockdown robustly affected spine morphology: spines with mature phenotype (i.e., “stubby” and “mushroom”) were significantly reduced in Cyfip1-silenced neurons compared to control, whereas elongated, immature-looking spines increased in number (Figures 5D, 5E, S5E, and S5F).”

May combine two claims.

The Rac1 inhibitor blocks the effects of BDNF and restores the equilibrium back to the more globular conformation.

“The Rac1 inhibitor blocked the effects of BDNF and restored the equilibrium back to the more globular conformation.”

May combine two claims.

The ratio of Cerulean-NCKAP1 over EYFP-CYFIP1 steadily increases in spines of BDNF-stimulated neurons, indicating a build-up of WRC.

“We observed that the ratio of Cerulean-NCKAP1 over EYFP-CYFIP1 steadily increases, indicating a build-up of WRC (Figure S3C).”

May combine two claims.

BDNF reduces the pool of CYFIP1 repressing translation and concomitantly increases the amount of CYFIP1 recruited on the WRC.

“BDNF, a neurotrophin and synaptic plasticity-inducing factor, able to induce protein synthesis (Takei et al., 2004) and cytoskeleton rearrangements (Bramham, 2008), reduces the pool of CYFIP1 repressing translation and concomitantly increases the amount of CYFIP1 recruited on the WRC.”

• cites Takei et al., 2004 sourceNot checked — no full text of the source
• cites Bramham, 2008 sourceNot checked — no full text of the source

May combine two claims.

Cotransfection of sh315 and Cyfip1 WT coding sequence restores normal CYFIP1 levels, proper spine distribution, and mean spine length.

“The construct was able to restore normal CYFIP1 levels (Figure S5E), and consequently proper spine distribution (Figures 5D, 5E, and S5F) and mean spine length (Figure 5F).”

May combine two claims.

Increasing concentrations of GTP-Rac1 reduce the binding of CYFIP1 to eIF4E, whereas GDP-Rac1 has no effect.

“Indeed, increasing concentrations of GTP-Rac1 reduced the degree of binding of CYFIP1 to eIF4E, whereas inactive Rac1 (GDP-Rac1) had no effect (Figure 2C).”

May combine two claims.

Inhibition of Rac1 activation before BDNF stimulation blocks ARC synthesis in WT and the residual synthesis in Fmr1 KO neurons, whereas no effect is observed in Cyfip1-silenced neurons.

“inhibition of Rac1 activation before BDNF stimulation blocked ARC synthesis in WT as well as the residual synthesis in Fmr1 KO neurons, whereas no effect was observed in Cyfip1-silenced neurons (Figure 3C).”

May combine two claims.

F-actin levels are rescued by mutant E, but not by mutant H.

“F-actin levels, in contrast, were rescued by mutant E, but not by mutant H.”

May combine two claims.

Mutant Δ and mutant H lose affinity for NCKAP1 and WAVE1 but not eIF4E, whereas mutant E decreases interaction with eIF4E, leaving NCKAP1 and WAVE1 unaffected.

“Both mutant Δ and mutant H lost their affinity for NCKAP1 and consequently for WAVE1, but not for eIF4E, whereas the interaction with eIF4E was largely decreased with mutant E (Figure 4A), leaving unaffected the binding to NCKAP1 and WAVE1.”

May combine two claims.

Mean head width is unchanged, but mean spine length is increased as a consequence of Cyfip1 silencing.

“Mean head width was unchanged (not shown), but mean spine length was increased as a consequence of Cyfip1 silencing; cumulative probability plots corroborated these results (Figure 5F).”

May combine two claims.

ARC is robustly upregulated after BDNF treatment in control, but not in Cyfip1-silenced neurons; NSC23766 does not affect ARC levels in CYFIP1-deficient cells.

“Moreover, ARC was robustly upregulated after BDNF treatment in control, but not in Cyfip1-silenced neurons; also the Rac1 inhibitor NSC23766 did not affect ARC levels in CYFIP1-deficient cells (Figure 3C).”

May combine two claims.

CYFIP1 downregulation causes augmented ARC synthesis and reduced F-actin levels in spines.

“We found that CYFIP1 downregulation caused augmented ARC synthesis and reduced F-actin levels in spines (Figure 4B).”

May combine two claims.

GTP-Rac1 also reduces the association of FMRP to eIF4E, with no changes for eIF4G.

“The association of FMRP to eIF4E was also reduced, whereas no changes were observed for eIF4G.”

May combine two claims.

Cotransfection of the construct carrying CYFIP1 WT rescues all defects, both basal and BDNF-induced.

“Cotransfection of the construct carrying CYFIP1 WT rescued all defects, both basal and BDNF-induced.”

May combine two claims.

In serum-deprived HEK293T cells, CYFIP1 and FMRP are rapidly released from eIF4E upon serum restoration and then slowly reassociate; Rac1 inhibitor abolishes the release.

“In agreement with our findings in brain, CYFIP1 and FMRP were rapidly released from eIF4E upon addition of serum, and then slowly reassociated (Figure S4B), whereas Rac1 inhibitor abolished the release of the translational inhibitory complex (Figure S4C).”

May combine two claims.

BDNF stimulation significantly reduces CYFIP1-eIF4E colocalization and increases CYFIP1-NCKAP1 puncta.

“Stimulation by BDNF significantly reduced the degree of CYFIP1-eIF4E colocalization, and concomitantly increased the number of CYFIP1-NCKAP1 puncta, suggesting that CYFIP1 distribution changes between these complexes upon TrkB receptor activation (Figures 2A and S2B).”

May combine two claims.

In mouse cortical synaptoneurosomes, 16 proteins co-immunoprecipitated with CYFIP1, seven of which had not been detected in the cortical lysate data set.

“Sixteen proteins were identified by MS, seven of which had not been detected in the cortical lysate data set”

May combine two claims.

RNase treatment of cortical lysates did not compromise CYFIP1 binding to PABP1, DCTN1, and eIF4E, but abolished its interaction with SYNCRIP, ELAVL4, and ELAVL1.

“Whereas the binding of CYFIP1 to PABP1, DCTN1 and eIF4E was not compromised by RNA degradation, the interaction with SYNCRIP, ELAVL4, and ELAVL1 was no longer detected (Figure 6C)”

• Also stated in: § CYFIP1 Interactome Is Linked to Human Disease · plain

  “CYFIP1 interactome is partially RNase sensitive.”

May combine two claims.

Altering CYFIP1 incorporation in the WRC (mutant H) affects F-actin polymerization but not ARC synthesis; conversely, impairing the CYFIP1-eIF4E interaction (mutant E) alters ARC synthesis with no effect on F-actin levels.

“Altering CYFIP1 incorporation in the WRC (as with mutant H) affects F-actin polymerization but not ARC synthesis; conversely, when the CYFIP1-eIF4E interaction is impaired (as with mutant E), ARC synthesis is altered with no effect on F-actin levels (Figure 4).”

May combine two claims.

Immunoprecipitation of NCKAP1 reveals CYFIP1 but not eIF4E, whereas immunoprecipitation of the eIF4E complex detects CYFIP1 but not NCKAP1.

“Furthermore, immunoprecipitation of NCKAP1 revealed the presence of CYFIP1 but not eIF4E, whereas immunoprecipitation of the eIF4E complex detected CYFIP1 but not NCKAP1 (Figure 1C).”

May combine two claims.

BDNF treatment attenuates the FRET signal, indicating a fraction of CYFIP1 molecules switched to the planar conformation.

“Treatment with BDNF attenuated the FRET signal, indicating that a fraction of CYFIP1 molecules switched to the planar conformation.”

May combine two claims.

CYFIP1 depletion severely affects dendritic spine morphology both in vivo and in vitro, causing an unbalanced ratio between mature and immature spines.

“We show here that CYFIP1 depletion severely affects dendritic spine morphology both in vivo and in vitro, causing an unbalanced ratio between mature and immature spines (Figures 4 and 5).”

May combine two claims.

Basal and inducible ARC expression is restored by mutant H, but not by mutant E.

“As predicted, basal and inducible ARC expression was restored by mutant H, but not by mutant E.”

May combine two claims.

The CYFIP1 interactome is enriched in genes implicated in ID, ASD, SCZ, ADHD, MDD, and AD; 25 out of 40 proteins that bind CYFIP1 are encoded by genes associated with these diseases, with 26% associated with schizophrenia, 19% with ASD, and 10% with ID.

“A literature search on disease involvement of the genes in question revealed that 25 out of the 40 proteins that bind CYFIP1 are encoded by genes associated with ID, ASD, ADHD, schizophrenia, major depressive disorder, and Alzheimer’s disease (Tables S4 and S5).”

• Also stated in: § CYFIP1 Interactome Is Linked to Human Disease · plain

  “In summary, 25 proteins out of 40 identified in our CYFIP1 interactome are encoded by genes involved in diseases: 26% are associated with schizophrenia, 19% with ASD, and 10% with ID (Table S4; Figure 6E).”

• Also stated in: § Discussion · plain

  “we find that the CYFIP1 interactome is enriched in genes implicated in ID, ASD, SCZ, ADHD, MDD, and AD.”

May combine two claims.

Downregulation of Cyfip1 causes defects in ARC synthesis and actin polymerization in dendritic spines.

“Downregulation of Cyfip1 causes defects in ARC synthesis and actin polymerization in dendritic spines (Figures 3 and 4).”

May combine two claims.

BDNF stimulation increases the amount of CYFIP1 coprecipitating with NCKAP1 and reduces its binding to eIF4E; Rac1 inhibitor prevents this redistribution.

“BDNF stimulation increased the amount of CYFIP1 coprecipitating with NCKAP1, and conversely reduced its binding to eIF4E; the Rac1 inhibitor was able to prevent the CYFIP1 redistribution (Figure 2B).”

May combine two claims.

ARC and F-actin are enhanced after BDNF treatment, but not in Cyfip1-silenced neurons.

“Moreover, ARC and F-actin were enhanced after BDNF treatment, but not in Cyfip1-silenced neurons (Figure 4B).”

May combine two claims.

Inhibition of Rac1 activation by NSC23766 further increases the FRET signal, most likely explained by a higher number of molecules in the more globular conformation.

“Inhibition of Rac1 activation by NSC23766 further increased the FRET signal, which is most likely explained by a higher number of molecules in the more globular conformation, the conformation that allows CYFIP1 to bind eIF4E.”

May combine two claims.

When CYFIP1 interacts with NCKAP1 forming a platform for the assembly of the WRC, the interaction with eIF4E is obstructed and vice versa.

“When CYFIP1 interacts with NCKAP1 forming a platform for the assembly of the WRC, the interaction with eIF4E is obstructed and vice versa.”

May combine two claims.

Concomitant to ARC induction, active Rac1 promotes CYFIP1 recruitment to the WRC and thus actin polymerization.

“Concomitant to ARC induction, active Rac1 promotes CYFIP1 recruitment to the WRC and thus actin polymerization.”

• AssumptionRests on an assumption: BDNF signaling activates Rac1 in neurons.

May combine two claims.

Correct spine morphology requires both intact CYFIP1-eIF4E and CYFIP1-WRC complexes, and correct coordination between the two is essential for proper ARC synthesis, actin polymerization, and finally spine morphology.

“Our studies reveal that correct spine morphology requires both intact CYFIP1-eIF4E and CYFIP1-WRC complexes, and that correct coordination between the two is essential for proper ARC synthesis, actin polymerization, and finally spine morphology (Figures 5 and 6).”

May combine two claims.

Fmr1 KO neurons silenced for Cyfip1 phenocopy CYFIP1-deficient neurons, confirming that FMRP and CYFIP1 act in the same pathway.

“Fmr1 KO neurons silenced for Cyfip1 phenocopied CYFIP1-deficient neurons, further confirming that FMRP and CYFIP1 act in the same pathway (Figure 3C).”

May combine two claims.

All these phenotypes overlap, without being identical, indicating that CYFIP1 is at the hub of more than one spine-controlling pathway.

“All these phenotypes overlap, without being identical, indicating that CYFIP1 is at the hub of more than one spine-controlling pathway.”

May combine two claims.

All mutants fail to restore normal spine distribution and spine length, indicating that both CYFIP1 complexes are equally important for proper spine formation.

“All mutants failed to restore the normal spine distribution and spine length (Figures 5D, 5F, and S5F), indicating that both CYFIP1 complexes are equally important for proper spine formation.”

May combine two claims.

BDNF-driven synaptic signaling releases CYFIP1 from the translational inhibitory complex, triggering translation of target mRNAs and shifting CYFIP1 into the WRC.

“Here, we show that brain-derived neurotrophic factor (BDNF)-driven synaptic signaling releases CYFIP1 from the translational inhibitory complex, triggering translation of target mRNAs and shifting CYFIP1 into the WAVE regulatory complex.”

May combine two claims.

Active Rac1 alters the CYFIP1 conformation, as demonstrated by intramolecular FRET, and is key in changing the equilibrium of the two complexes.

“Active Rac1 alters the CYFIP1 conformation, as demonstrated by intramolecular FRET, and is key in changing the equilibrium of the two complexes.”

Classified as probably not a substantial claim.

Genetic alterations of the pathways controlling local protein synthesis in neurons contribute to diverse intellectual disabilities and autism spectrum disorders.

“Genetic alterations of the pathways controlling local protein synthesis in neurons contribute to diverse intellectual disabilities (ID) and autism spectrum disorders (ASDs) (Ehninger and Silva, 2009).”

• cites Ehninger and Silva, 2009 sourceNot checked — no full text of the source

Classified as probably not a substantial claim.

To exclude off-target effects, a rescue experiment was performed by cotransfecting sh315 and the Cyfip1 WT coding sequence.

“To exclude the possibility that the phenotype might be due to off-target effects, we performed a rescue experiment by cotransfecting the sh315 (against Cyfip1 3′UTR) and the Cyfip1 WT coding sequence.”

May combine two claims.

As a consequence of BDNF/Rac1 signaling, CYFIP1 is freed from eIF4E and the synthesis of key modulators of synaptic plasticity such as ARC is activated.

“As a consequence, CYFIP1 is freed from eIF4E and the synthesis of key modulators of synaptic plasticity such as ARC is activated (Figure 6F).”

• AssumptionRests on an assumption: BDNF signaling activates Rac1 in neurons.

May combine two claims.

CYFIP1 deficiency alters the proper functioning of two complexes modulating critical synaptic processes, protein synthesis and actin cytoskeleton remodeling, both ultimately leading to defects in spine morphology.

“In conclusion, CYFIP1 deficiency alters the proper functioning of two complexes modulating critical synaptic processes, i.e., protein synthesis and actin cytoskeleton remodeling, both of these ultimately leading to defects in spine morphology.”

May combine two claims.

Activated Rac1 reshapes the CYFIP1-eIF4E complex through a conformational change, so that when translation inhibition is lifted, more CYFIP1 becomes available for the WRC.

“Activated Rac1 reshapes the CYFIP1-eIF4E complex through a conformational change, so that when translation inhibition is lifted, more CYFIP1 becomes available for the WRC.”

May combine two claims.

CYFIP1 orchestrates protein translation and actin polymerization, each of which is necessary for correct spine morphology in neurons.

“CYFIP1 thus orchestrates the two molecular cascades, protein translation and actin polymerization, each of which is necessary for correct spine morphology in neurons.”

May combine two claims.

CYFIP1 is present in two functional complexes essential for synaptic morphology and function: a ribonucleoparticle repressing protein synthesis and the WAVE regulatory complex.

“CYFIP1 is present in two functional complexes essential for synaptic morphology and function: a ribonucleoparticle repressing protein synthesis and the WAVE regulatory complex (Figure 6F).”

May combine two claims.

CYFIP1 is active in regulating mRNA translation and determining cytoskeleton-based cell morphology.

“These results further demonstrate that CYFIP1 is active in regulating mRNA translation and determining cytoskeleton-based cell morphology.”

May combine two claims.

Mutations in the genes of the CYFIP1 interactome might perturb the homeostasis of the interaction networks, regulating translation versus cytoskeleton remodeling, thereby triggering a spectrum of pathological processes at synapses that can lead to a broad range of clinical manifestations, such as intellectual disabilities, autism, and schizophrenia.

“Mutations in the genes of the CYFIP1 interactome might perturb the homeostasis of the interaction networks, regulating translation versus cytoskeleton remodeling, thereby triggering a spectrum of pathological processes at synapses that can lead to a broad range of clinical manifestations, such as intellectual disabilities, autism, and schizophrenia.”

• AssumptionRests on an assumption: The mouse cortical CYFIP1 interactome is representative of the human CYFIP1 interactome in relevant disease contexts.

Classified as probably not a substantial claim.

Counts and data analysis were conducted blind to experimental condition.

“Counts and data analysis were conducted blind to experimental condition.”

Classified as probably not a substantial claim.

At least ten randomly chosen neurons per condition from three independent cultures were imaged for quantification.

“At least ten randomly chosen neurons/condition from three independent cultures were imaged for quantification.”