The DOI matches its Crossref record; 113 of the 117 references it cites were found in a registry or an index; 2 of the 47 sources its claims cite were checked for support.
A Highly Conserved Program of Neuronal Microexons Is Misregulated in Autistic Brains
Open accessAbstract
Summary Alternative splicing (AS) generates vast transcriptomic and proteomic complexity. However, which of the myriad of detected AS events provide important biological functions is not well understood. Here, we define the largest program of functionally coordinated, neural-regulated AS described to date in mammals. Relative to all other types of AS within this program, 3-15 nucleotide ‘microexons’ display the most striking evolutionary conservation and switch-like regulation. These microexons modulate the function of interaction domains of proteins involved in neurogenesis. Most neural microexons are regulated by the neuronal-specific splicing factor nSR100/SRRM4, through its binding to adjacent intronic enhancer motifs. Neural microexons are frequently misregulated in the brains of individuals with autism spectrum disorder, and this misregulation is associated with reduced levels of nSR100. The results thus reveal a highly conserved program of dynamic microexon regulation associated with the remodeling of protein interaction networks during neurogenesis, the misregulation of which is linked to autism.
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This paper defines a large neural-regulated alternative splicing program in mammals, showing that 3–27 nucleotide microexons are exceptionally conserved, dynamically regulated during neuronal differentiation, and often controlled by nSR100/SRRM4. It further reports that microexons are frequently misregulated in autistic brains and that this misregulation correlates with reduced nSR100 expression.
Key findings
- Across human and mouse cell/tissue datasets, the authors identified about 2,500 neural-regulated AS events per species; microexons showed stronger neural-specific inclusion than longer exons (60.7% of microexons with ΔPSI>15 versus 9.5% of longer exons).
- Of 308 human neural-regulated microexons, 225 (73.5%) were also neural-differentially spliced in mouse, compared with 527 of 1,390 (37.9%) longer neural-regulated exons; many microexons were deeply conserved across vertebrates.
- During mouse ES-cell-to-cortical-neuron differentiation, 151 of 219 profiled neural-regulated microexons (69%) showed a PSI switch ≥50, and 65 (30%) showed a switch ≥90; nSR100 knockdown/overexpression affected more than half of profiled microexons.
- In ASD post-mortem superior temporal gyrus samples, 126 of 504 detected microexons (30%) had mean ΔPSI>10 between ASD and control, versus 825 of 15,405 longer exons (5.4%); nSR100 mRNA was downregulated on average by about 10% in ASD samples (p=0.014).
Methods
- The authors developed an RNA-Seq analysis pipeline to detect all AS classes, including microexons, and applied it to deep datasets from more than 50 human and mouse cell/tissue types, developmental stages, and several vertebrate species.
- They analyzed microexon regulation across six time points of mouse embryonic stem cell differentiation into cortical glutamatergic neurons, and used knockdown/overexpression plus PAR-iCLIP data to test nSR100/SRRM4 regulation.
- Protein interaction effects were tested with LUMIER assays and co-immunoprecipitation-western blotting for Apbb1 and AP1S2 microexons; ASD analyses used 24 autistic individuals and 24 matched controls, with 12 ASD samples showing the strongest ASD-associated expression signature and 12 controls selected for downstream comparisons.
Limitations
- The paper does not state a dedicated limitations section.
- Evident from the text: the ASD splicing analysis focused on a selected subset of 12 ASD and 12 control samples stratified by a pre-existing ASD gene-expression signature, so findings may not generalize to all autistic individuals.
- Evident from the text: the link between reduced nSR100 and microexon misregulation in ASD is correlational, and the authors do not establish causation; microexon detection also depends on a specialized pipeline and sufficient RNA-Seq read coverage.
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67 Own result · 25 Not checked yet · 17 Own interpretation · 4 Own method · 2 No basis given · 1 Partly supported · accuracy not yet measured
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Here, we define the largest program of functionally coordinated, neural-regulated AS described to date in mammals.”
- Also stated in: § Global features of neural-regulated AS · plain
“These data reveal the largest program of neural-regulated AS events defined to date, and that this program is associated with a broader range of functional processes and pathways linked to nervous system biology than previously detected (Boutz et al., 2007; Fagnani et al., 2007; Ule et al., 2005).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Abstract
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- Also stated in: § Global features of neural-regulated AS · plain
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“Further analysis of the neural-regulated AS program revealed a striking inverse relationship between the length of an alternative exon and its propensity to be specifically included in neural tissues.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Highly conserved microexons are frequently neural specific
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“Nearly half of the neural-regulated AS events, including alternative retained introns, are predicted to generate protein isoforms both when the alternative sequence is included and skipped.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Global features of neural-regulated AS
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“In contrast, only ∼20% of AS events not subject to neural regulation (hereafter ‘non-neural’ events) have the potential to generate alternative protein isoforms (Figure 1B; p=2.7×10-248, proportion test).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Global features of neural-regulated AS
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“By applying this pipeline to more than 50 diverse cell and tissue types each from human and mouse (Table S1), we identified ∼2,500 neural-regulated AS events in each species (Figure 1A and Table S2; Extended Experimental Procedures).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Global features of neural-regulated AS
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“This trend extends to microexons as short as 3 nt.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Highly conserved microexons are frequently neural specific
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“Gene Ontology (GO) analysis shows that genes with neural-regulated AS events predicted to generate alternative protein isoforms form highly interconnected networks based on functions associated with neuronal biology, signaling pathways, structural components of the cytoskeleton and the plasma membrane (Figure 1C).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Global features of neural-regulated AS
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“Neural microexons are frequently misregulated in the brains of individuals with autism spectrum disorder, and this misregulation is associated with reduced levels of nSR100.”
- Also stated in: § Microexons are misregulated in individuals with Autism Spectrum Disorder · plain
“These data reveal frequent misregulation of microexon splicing in the brain cortices of some individuals with ASD.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Abstract
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“Relative to longer alternative exons, microexons, in particular those that are 3-15-nt long and neural-specifically included, are strongly enriched in multiple features indicative of functionally important AS.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Highly conserved microexons are frequently neural specific
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“the vast majority (>90%) of neural-regulated microexons display highest PSIs in neurons compared to all other cell and tissue types analyzed (Figure S2B-D, and Supplemental Information).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Highly conserved microexons are frequently neural specific
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“and this misregulation is associated with reduced levels of nSR100.”
- Also stated in: § Introduction · plain
“this misregulation is linked to the reduced expression of the neural-specific Ser/Arg-related splicing factor of 100kDa, nSR100/SRRM4.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Abstract
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“Most neural microexons are regulated by the neuronal-specific splicing factor nSR100/SRRM4, through its binding to adjacent intronic enhancer motifs.”
- Also stated in: § The neural-specific splicing factor nSR100/SRRM4 regulates most neural microexons · boosted
“nSR100 thus has a direct and extensive role in the regulation of the neural microexon program.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Abstract
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“Moreover, when not overlapping protein domains, microexons are significantly more often located immediately adjacent (i.e. within 5 amino acids) to folded protein domains (Figures 5E and S5J,K).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Distinct protein regulatory properties of microexons
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“Relative to longer exons, we additionally observe that neural-regulated microexons are associated with weak 3′ splice sites and strong 5′ splice sites (Figure S4J).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > The neural-specific splicing factor nSR100/SRRM4 regulates most neural microexons
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“Neural-regulated microexons are significantly enriched in domains that function in peptide and lipid-binding interactions (Figures 5F and S5L; p = 1.7×10-6, proportion test).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons modulate the function of interaction domains
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“They are highly enriched for lengths that are multiples of three nts (Figure 2B), and a significantly larger fraction are predicted to generate alternative protein isoforms upon inclusion and exclusion, compared with longer exons (Figure 2C; p<10-10, proportion test).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Highly conserved microexons are frequently neural specific
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“Consistent with their striking regulatory conservation, sequences overlapping microexons, including both the upstream and downstream flanking intronic regions, are more highly conserved than sequences surrounding longer alternative exons (Figure 2F, S2G), including longer exons with a similar distribution of neural versus non-neural ΔPSI values (Figure S2H,I; data not shown).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Highly conserved microexons are frequently neural specific
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“Remarkably, within these samples, 126 of 504 (30%) detected alternative microexons display a mean ΔPSI > 10 between ASD and control subjects (Figure 7A), of which 113 (90%) also display neural-differential regulation.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons are misregulated in individuals with Autism Spectrum Disorder
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“Exemplifying the distinct protein features of neural microexons described above (Figure 5), the Apbb1 microexon adds two charged residues (Arg and Glu) to the PTB1 domain near its predicted interaction surface (Figures 6A,B; Extended Experimental Procedures).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons modulate the function of interaction domains
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“However, only 26.9% (32/119) of the genes containing misregulated microexons overlapped with the 2,519 genes with significant ASD-associated misregulation at the level of gene expression.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons are misregulated in individuals with Autism Spectrum Disorder
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“Similar results were observed when analyzing data from a different brain region (Brodmann area ba9) from the same individuals (data not shown).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons are misregulated in individuals with Autism Spectrum Disorder
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“Most microexons show sharp PSI switches at late (T3 to T5) transitions during differentiation.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Dynamic regulation of microexons during neuronal differentiation
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“Analysis of the proportions of microexons displaying coincident misregulation revealed that the vast majority (81.3%) have a ΔPSI>10 in at least half of the ASD stratified brain samples (Figure S7C).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons are misregulated in individuals with Autism Spectrum Disorder
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“Significant enrichment for misregulation among microexons compared to longer exons was also observed when restricting the analysis to neural-regulated exons, including subsets of neural-regulated microexons and longer exons with similar distributions of neural versus non-neural ΔPSI values (Figure S7A; p<2×10-4, proportion test; data not shown).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons are misregulated in individuals with Autism Spectrum Disorder
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“of which 285 (35%) correspond to neural-regulated exons.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons are misregulated in individuals with Autism Spectrum Disorder
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“Co-immunoprecipitation-western analyses reveal that the microexon in AP1S2 strongly promotes its interaction with another AP1 subunit, AP1B1 (Figure 6E and S6D).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons modulate the function of interaction domains
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“By contrast, only 825 of 15,405 (5.4%) longer (i.e. >27 nt) exons show such misregulation (Figure 7A), of which 285 (35%) correspond to neural-regulated exons.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons are misregulated in individuals with Autism Spectrum Disorder
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“Unsupervised hierarchical clustering of PSI changes between consecutive time points (transitions T1 to T5) revealed several temporally-distinct regulatory patterns (Figure 3A).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Dynamic regulation of microexons during neuronal differentiation
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“whereas a significantly higher fraction overlap modular protein domains (Figures 5B and S5E; ∼2-fold increase, p=1.0×10-54, proportion test).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Distinct protein regulatory properties of microexons
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“A significantly smaller fraction overlap predicted disordered amino acid residues (Figures 5A and S5A-D; p < 1.3×10-4; 3-way Fisher Exact tests), whereas a significantly higher fraction overlap modular protein domains (Figures 5B and S5E; ∼2-fold increase, p=1.0×10-54, proportion test).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Distinct protein regulatory properties of microexons
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“Consistent with these results, and supporting a direct role for nSR100 in microexon regulation, RNA sequence tags cross-linked to nSR100 in vivo are also highly enriched in intronic sequences containing UGC motifs, located adjacent to the 3′ splice sites of nSR100-regulated microexons (Figure 4B, C; p<0.0001 for all comparisons, Wilcoxon Rank Sum test).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > The neural-specific splicing factor nSR100/SRRM4 regulates most neural microexons
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“Moreover, of ∼150 analyzed mammalian, neural-regulated, 3-15-nt microexons, at least 55 are deeply conserved in vertebrate species spanning 400-450 million years of evolution, from zebrafish and/or shark to human (Table S3).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Highly conserved microexons are frequently neural specific
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“of which 113 (90%) also display neural-differential regulation.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons are misregulated in individuals with Autism Spectrum Disorder
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“Conversely, unlike longer neural exons (Buljan et al., 2012; Ellis et al., 2012), they are depleted of linear binding motifs (Figure 5G and S5N, p<0.005, proportion tests for all comparisons).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons modulate the function of interaction domains
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“Overall, genes with microexons are highly enriched in modular domains involved in cellular signaling, such as SH3 and PH domains (Figure S5M).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons modulate the function of interaction domains
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“Neural-regulated microexons, in particular those that are 3-15-nt long, possess multiple properties that distinguish them from longer neural-regulated exons (Figures 5 and S5).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Distinct protein regulatory properties of microexons
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“Moreover, an analysis of RNA-Seq data from different neural cell types (Zhang et al., 2014) revealed that nSR100 has the strongest neuronal-specific expression relative to the other splicing regulators (Figure S4I, and data not shown), which is also consistent with its immunohistochemical detection in neurons but not glia (Calarco et al., 2009).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > The neural-specific splicing factor nSR100/SRRM4 regulates most neural microexons
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plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“a significantly larger fraction are predicted to generate alternative protein isoforms upon inclusion and exclusion, compared with longer exons (Figure 2C; p<10-10, proportion test).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Highly conserved microexons are frequently neural specific
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In the paper
“neural microexons are significantly enriched in surface-accessible, charged amino acids that overlap or lie in close proximity to protein domains, including those that bind linear motifs”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Discussion
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In the paper
“including the microexon in AP1S2 that strongly promotes an interaction with the AP1B1 subunit of the AP1 intracellular transport complex”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Discussion
boosteddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“it controls the switch-like regulation of most neural microexons”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Discussion
plaindirect- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: nSR100 mRNA expression levels reflect nSR100 protein activity or functional nSR100 levels.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“A GO analysis of genes with ASD-associated misregulation of microexons reveals significant enrichment of terms related to axonogenesis and synapse biology (Figure 7E)”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons are misregulated in individuals with Autism Spectrum Disorder
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: The ASD and control brain samples analyzed are representative of the broader ASD and control populations.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“its reduced expression is linked to the altered splicing of microexons in the brains of subjects with ASD”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: The ASD and control brain samples analyzed are representative of the broader ASD and control populations.
- Rests on an assumption: nSR100 mRNA expression levels reflect nSR100 protein activity or functional nSR100 levels.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“we show that a 6 nt neural microexon in Apbb1/Fe65 promotes an interaction with Kat5/Tip60”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Discussion
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In the paper
“we also observe significantly higher correlations between microexon inclusion and nSR100 mRNA expression levels across the stratified ASD samples and controls, for those microexons regulated by nSR100 relative to those microexons that are not regulated by this factor (Figure 7D; p=1.4×10-7, Wilcoxon Sum Rank test)”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons are misregulated in individuals with Autism Spectrum Disorder
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: The ASD and control brain samples analyzed are representative of the broader ASD and control populations.
- Rests on an assumption: nSR100 mRNA expression levels reflect nSR100 protein activity or functional nSR100 levels.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“misregulated microexons are also significantly enriched in genes that have been genetically linked to ASD (p < 0.0005, Fisher exact test)”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons are misregulated in individuals with Autism Spectrum Disorder
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the microexons we have analyzed in APBB1 and AP1S2 are significantly misregulated in the brain samples from ASD subjects (p<0.05 Wilcoxon Sum Rank test; Figure S7E)”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons are misregulated in individuals with Autism Spectrum Disorder
plaincorrelational- Asserted: passes — The authors put it forward as true.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In contrast, a comparison of autistic subjects that possessed a weaker ASD-related differential gene expression signature did not reveal significant misregulation of microexons, or of longer exons (data not shown).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons are misregulated in individuals with Autism Spectrum Disorder
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In the paper
“several other genes containing microexons are genetically linked to ASD, intellectual disability and/or functions in memory and learning (see Results)”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: Several genes with misregulated microexons have been linked to learning or intellectual disability.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“relative to other exons, nSR100-dependent microexons are significantly more often misregulated in brain tissues from ASD compared to control subjects (Figure 7C; p<0.01 for all comparisons, proportion test)”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons are misregulated in individuals with Autism Spectrum Disorder
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: The ASD and control brain samples analyzed are representative of the broader ASD and control populations.
- Rests on an assumption: nSR100 mRNA expression levels reflect nSR100 protein activity or functional nSR100 levels.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“the microexon in APBB1 is also significantly misregulated in brain tissues from ASD subjects (Figure S7B,E)”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: The ASD and control brain samples analyzed are representative of the broader ASD and control populations.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“and to an even greater extent in brain samples with the strongest ASD-associated signature compared to the controls (∼10%, p=0.014, FDR<0.1, Figure 7B and data not shown)”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons are misregulated in individuals with Autism Spectrum Disorder
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: The ASD and control brain samples analyzed are representative of the broader ASD and control populations.
- Rests on an assumption: nSR100 mRNA expression levels reflect nSR100 protein activity or functional nSR100 levels.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“nSR100 mRNA expression is, on average, significantly downregulated in the brains of the analyzed ASD versus control subjects”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons are misregulated in individuals with Autism Spectrum Disorder
plain- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: The ASD and control brain samples analyzed are representative of the broader ASD and control populations.
- Rests on an assumption: nSR100 mRNA expression levels reflect nSR100 protein activity or functional nSR100 levels.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Many of the conserved, neural-regulated microexons identified in this study are misregulated in ASD individuals”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Rests on an assumption: The ASD and control brain samples analyzed are representative of the broader ASD and control populations.
None of the sources cited for this claim have been checked yet.
In the paper
“Most microexons display high inclusion at late stages of neuronal differentiation in genes (e.g. Src (Black, 1991), Bin1, Agrn, Dock9, Shank2, Robo1) associated with axonogenesis and the formation and function of synapses.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Discussion
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In the paper
“These observations suggested that a widespread role for regulated exons is to specify cell and tissue type-specific protein interaction networks.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Introduction
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In the paper
“These microexons modulate the function of interaction domains of proteins involved in neurogenesis.”
- Also stated in: § Distinct protein regulatory properties of microexons · hedged
“These results suggest that a common function of microexons may be to modulate the activity of overlapping or adjacent protein domains.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Abstract
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- Also stated in: § Distinct protein regulatory properties of microexons · hedged
In the paper
“Furthermore, where alignment tools have been developed to capture microexons (Wu et al., 2013), they have not been applied to the analysis of different cell and tissue types, or disease states.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Introduction
What the sources say
- Not checked yetcites Wu et al., 2013
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In the paper
“These results indicate that tissue-regulated microexons are predominately neuronal-specific.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Highly conserved microexons are frequently neural specific
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“RT-PCR validation experiments confirmed the RNA-Seq-detected regulatory profiles and inclusion levels of all (10/10) microexons analyzed across ten diverse tissues (R2 = 0.92, n=107; Figure S2A).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Highly conserved microexons are frequently neural specific
plaincorrelationaln = 107- Asserted: passes — The authors put it forward as true.
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In the paper
“In particular, microexons (Beachy et al., 1985; Coleman et al., 1987), defined here as 3-27 nucleotide (nt)-long exons, have been largely missed by genome annotations and transcriptome profiling studies (Volfovsky et al., 2003; Wu et al., 2013; Wu and Watanabe, 2005). This is especially true for microexons shorter than 15 nts.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Introduction
What the sources say
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“This suggests that the primary function of this microexon is to extend the interface with which Apbb1 binds its partner proteins.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons modulate the function of interaction domains
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In the paper
“RT-PCR experiments on a representative subset of profiled tissues confirmed increased misregulation of microexons in autistic versus control brain samples (Figure S7B).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons are misregulated in individuals with Autism Spectrum Disorder
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“This observation thus provides additional evidence supporting an important role for microexons in the control of protein interactions that function in neurons.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons modulate the function of interaction domains
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“This pattern of late activation (Figure S3B) suggests enrichment for important functions for microexons in terminal neurogenesis (Figure 1C).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Dynamic regulation of microexons during neuronal differentiation
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These results suggest that a common function of microexons may be to modulate the activity of overlapping or adjacent protein domains.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Distinct protein regulatory properties of microexons
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Taken together with the data in Figure 1, these results suggest that microexons may often regulate interaction domains to facilitate the remodeling of protein interaction networks associated with signaling and other aspects of neuronal maturation and function.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons modulate the function of interaction domains
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In the paper
“These observations indicate that the dynamic switch-like regulation of microexons is intimately associated with the maturation of neurons.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Dynamic regulation of microexons during neuronal differentiation
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“nSR100 thus has a direct and extensive role in the regulation of the neural microexon program.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > The neural-specific splicing factor nSR100/SRRM4 regulates most neural microexons
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“This reveals that largely distinct subsets of genes are misregulated at the levels of expression and microexon splicing in the analyzed ASD subjects.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons are misregulated in individuals with Autism Spectrum Disorder
plaincorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“These data reveal frequent misregulation of microexon splicing in the brain cortices of some individuals with ASD.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons are misregulated in individuals with Autism Spectrum Disorder
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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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
“These differences were confirmed by qRT-PCR assays for a representative subset of individuals (p<2.8×10-4 for all normalizations; two-sided T-test; Figure S7D)”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons are misregulated in individuals with Autism Spectrum Disorder
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: nSR100 mRNA expression levels reflect nSR100 protein activity or functional nSR100 levels.
In the paper
“nSR100 is strongly co-expressed in the developing human brain in a gene network module, M2, which is enriched for rare de novo ASD-associated mutations (Parikshak et al., 2013)”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Discussion
What the sources say
- Not checked yetcites Parikshak et al., 2013 source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“these observations suggest that microexons contribute important and complementary roles to longer neural exons in the remodeling of protein interaction networks that operate during neuronal maturation”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Discussion
hedgeddirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Disruption of microexon-regulated protein interaction networks is therefore a potentially important mechanism underlying ASD and likely other neurodevelopmental disorders.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons are misregulated in individuals with Autism Spectrum Disorder
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: The ASD and control brain samples analyzed are representative of the broader ASD and control populations.
- It may state two separate claims as one. 28
- Probably not a substantial claim. 19
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“the results suggest that the misregulation of microexons, as well as of longer alternative exons (Corominas et al., 2014; Voineagu et al., 2011), may impact protein interaction networks that are required for normal neuronal development and synaptic function”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons are misregulated in individuals with Autism Spectrum Disorder
What the sources say
- Partly supportedcites Corominas et al., 2014 sourceExperimental — accuracy not yet measured
The Results section, “Splicing isoform interactions expand ASIN” (page unavailable), reports that inclusion or exclusion of specific exons changes protein interaction partners and suggests that differential exon usage can alter interaction networks. Our copy does not establish the claim about microexon misregulation or show that the affected networks are required for normal neuronal development and synaptic function. (LLM, conf=0.84)
- Partly supportedcites Voineagu et al., 2011 sourceExperimental — accuracy not yet measured
The paper reports differential splicing of alternative exons in ASD brain (p. 5) and says many affected exons belong to genes involved in synaptic function (p. 6). It does not identify microexons or longer exons as distinct groups, or link their misregulation to protein interaction networks required for neuronal development. (LLM, conf=0.85)
hedgedconditional- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The ASD and control brain samples analyzed are representative of the broader ASD and control populations.
- Partly supported
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Relative to all other types of AS within this program, 3-15 nucleotide ‘microexons’ display the most striking evolutionary conservation and switch-like regulation.”
- Also stated in: § Introduction · boosted
“Strikingly, neural-included microexons represent the most highly conserved and dynamically-regulated component of this program, and the corresponding genes are highly enriched in neuronal functions.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Abstract
boostedcorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Also stated in: § Introduction · boosted
None of the sources cited for this claim have been checked yet.
In the paper
“Consistent with previous results (Fagnani et al., 2007; Pan et al., 2004), there is little overlap (8.5%) between genes with neural-regulated AS and mRNA expression, although these subsets of genes are highly enriched in overlapping GO terms (40% in common; Figure S1).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Global features of neural-regulated AS
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“60.7% of alternative microexons show increased neural ‘percent spliced in’ (PSI) (ΔPSI>15) versus 9.5% of longer (average ∼135 nt) alternative exons (p=1.9×10-220, proportion test).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Highly conserved microexons are frequently neural specific
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Supporting this view, among 49 available and de novo-modeled tertiary protein structures containing microexons, the corresponding residues are largely surface accessible amd unlikely to significantly affect the folding of the overlapping or adjacent protein domains (Figure S6A; Extended Experimental Procedures).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Distinct protein regulatory properties of microexons
hedged- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“They are also significantly more often conserved at the levels of genomic sequence, detection in alternatively spliced transcripts, and neural-differential regulation (Figure 2D; Figure S2E, neural-regulated exons; p<0.001 for all pairwise comparisons, proportion tests.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Highly conserved microexons are frequently neural specific
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Among several analyzed splicing regulators (Extended Experimental Procedures), knockdown and overexpression of nSR100 had the strongest effect on microexon regulation, with more than half of the profiled microexons displaying a pronounced change in inclusion level compared to controls (Figure 4A and S4A-S4H).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > The neural-specific splicing factor nSR100/SRRM4 regulates most neural microexons
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Moreover, proteins containing microexons are significantly more often central in protein-protein interaction networks and detected in protein complexes compared to proteins with other types of alternative exons (Figures 5H and S5O,P, p≤0.004 for all comparisons, Wilcoxon Rank Sum test).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons modulate the function of interaction domains
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Of 308 neural-regulated microexons in human, 225 (73.5%) are neural-differentially spliced in mouse, compared to only 527 of 1390 (37.9%) longer neural-regulated exons.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Highly conserved microexons are frequently neural specific
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Despite the small number of genes representing clusters of kinetically-distinct sets of regulated microexons, each cluster revealed significant enrichment of specific GO terms including “regulation of GTPase activity” (Cluster I), “glutamate receptor binding” and “actin cytoskeleton organization” (Cluster V) (Table S4).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Dynamic regulation of microexons during neuronal differentiation
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Remarkably, while microexons represent only ∼1% of all AS events, they comprise approximately one third of all neural-regulated AS events conserved between human and mouse that are predicted to generate alternative protein isoforms (Figure S2F).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Highly conserved microexons are frequently neural specific
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In contrast, microexon residues overlapping protein domains are significantly more often surface-accessible and enriched in charged residues (Figures 5C,D, and S5F-I; p<10-7 for all comparisons, proportion test) than are residues overlapping longer neural or non-neural exons.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Distinct protein regulatory properties of microexons
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Substitution of both microexon residues with alanine also enhanced the Kat5 interaction, although to a lesser extent than the presence of Arg and Glu (Figure 6C).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons modulate the function of interaction domains
plaindirect- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“LUMIER and co-immunoprecipitation-western analysis reveals that inclusion of the microexon significantly enhances the interaction with Kat5, whereas there is little to no effect on the interaction with App (Figures 6C,D and Figure S6B,C).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons modulate the function of interaction domains
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“These stages correspond to maturing post-mitotic neurons when pan-neuronal markers are already expressed, and are subsequent to the expression of most neurogenic transcription factors (Figure S3A).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Dynamic regulation of microexons during neuronal differentiation
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Remarkably, of 219 neural-regulated microexons with sufficient read coverage across time points, 151 (69%) displayed a PSI switch ≥ 50 between ES cells and mature neurons, and 65 (30%) a switch of ≥ 90 (Figure 3).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Dynamic regulation of microexons during neuronal differentiation
plain- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Furthermore, comparable numbers of alternative microexons were detected in all analyzed vertebrate species, the majority of which are also strongly neural-specifically included (Figure 2E; Supplemental Information for details).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Highly conserved microexons are frequently neural specific
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“alternative microexons display the highest degrees of genomic sequence conservation, tissue-specific regulatory conservation, and frame-preservation potential, relative to all other classes of AS detected to date in vertebrate species”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Many of the corresponding genes act in common pathways and/or physically interact through protein-protein interactions (Figure 7F)”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons are misregulated in individuals with Autism Spectrum Disorder
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
- Rests on an assumption: The ASD and control brain samples analyzed are representative of the broader ASD and control populations.
None of the sources cited for this claim have been checked yet.
In the paper
“An important advance that is facilitating a more general understanding of the role of individual AS events is the observation that many cell/tissue type- and developmentally-regulated AS events are coordinately controlled by individual RBPs, and that these events are significantly enriched in genes that operate in common biological processes and pathways (Calarco et al., 2011; Irimia and Blencowe,”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Introduction
What the sources say
- Not checked yetcites Calarco et al., 2011 source
- Not checked yetcites Irimia and Blencowe, 2012
- Not checked yetcites Licatalosi and Darnell, 2010
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Alternative splicing (AS) – the process by which different pairs of splice sites are selected in precursor mRNA to generate multiple mRNA and protein products – is responsible for greatly expanding the functional and regulatory capacity of metazoan genomes (Braunschweig et al., 2013; Chen and Manley, 2009; Kalsotra and Cooper, 2011).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Introduction
What the sources say
- Not checked yetcites Braunschweig et al., 2013 source
- Not checked yetcites Chen and Manley, 2009
- Not checked yetcites Kalsotra and Cooper, 2011
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The results thus reveal a highly conserved program of dynamic microexon regulation associated with the remodeling of protein interaction networks during neurogenesis, the misregulation of which is linked to autism.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Abstract
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It may state two separate claims as one.
In the paper
“Indeed, among a set of analyzed neural-specific exons enriched in disordered regions, approximately one third promoted or disrupted interactions with partner proteins (Ellis et al., 2012).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Introduction
What the sources say
- Not checked yetcites Ellis et al., 2012 source
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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Probably not a substantial claim.
In the paper
“changes in the expression of the RBP RBFOX1 have been linked to misregulation of AS in the brains of individuals with autism spectrum disorder (ASD) (Voineagu et al., 2011).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Introduction
What the sources say
- Not checked yetcites Voineagu et al., 2011 source
plaincorrelational- Asserted: passes — The authors put it forward as true.
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- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“These data reveal the largest program of neural-regulated AS events defined to date, and that this program is associated with a broader range of functional processes and pathways linked to nervous system biology than previously detected (Boutz et al., 2007; Fagnani et al., 2007; Ule et al., 2005).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Global features of neural-regulated AS
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Human disease mutations often disrupt cis-elements that control splicing and result in aberrant AS patterns (Cartegni et al., 2002).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Introduction
What the sources say
- Not checked yetcites Cartegni et al., 2002 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“However, the function of the vast majority of AS events detected to date are not known, and new landscapes of AS regulation remain to be discovered and characterized(Braunschweig et al., 2014; Eom et al., 2013).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Introduction
What the sources say
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“Other disease changes affect the activity or expression of RBPs, causing entire programs of AS to be misregulated.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Introduction
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
None of the sources cited for this claim have been checked yet.
In the paper
“While cell and tissue differentially-regulated AS events are significantly under-represented in functionally defined, folded domains in proteins, they are enriched in regions of protein disorder that typically are surface accessible and embed short linear interaction motifs (Buljan et al., 2012; Ellis et al., 2012; Romero et al., 2006).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Introduction
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Recently, we have shown that nSR100 promotes the inclusion of a subset of (longer) neural exons via binding to intronic UGC motifs proximal to suboptimal 3′ splice sites (Raj et al., 2014).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > The neural-specific splicing factor nSR100/SRRM4 regulates most neural microexons
What the sources say
- Not checked yetcites Raj et al., 2014 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Interestingly, mutations in AP1S2 have been previously implicated in phenotypic features associated with ASD and X-linked mental retardation (Borck et al., 2008; Tarpey et al., 2006).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons modulate the function of interaction domains
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The properties of microexons described above suggest that their misregulation could be associated with neurological disorders.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons are misregulated in individuals with Autism Spectrum Disorder
hedgedcorrelationaln = 12- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
- Rests on an assumption: Misregulation of alternative splicing frequently causes or contributes to human disease.
None of the sources cited for this claim have been checked yet.
In the paper
“The AP1 complex functions in the intracellular transport of cargo proteins between the trans-Golgi apparatus and endosomes by linking clathrin to the cargo proteins during vesicle membrane formation (Kirchhausen, 2000), and is important for the somatodendritic transport of proteins required for neuronal polarity (Farias et al., 2012).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons modulate the function of interaction domains
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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Probably not a substantial claim. It may state two separate claims as one.
In the paper
“Apbb1 contains two phosphotyrosine binding domains, PTB1 and PTB2, which bind Kat5 and App, respectively (Cao and Sudhoff, 2001).”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons modulate the function of interaction domains
What the sources say
- Not checked yetcites Cao and Sudhoff, 2001
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
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
“Sample selection was independent of any information on splicing changes.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Experimental Procedures > Comparison of ASD and control brain samples
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“an alternative microexon overlapping the SH3A domain of Intersectin 1 (Itsn1) has been reported to promote an interaction with Dynamin 1, and was proposed to modulate roles of Itsn1 in endocytosis, cell signaling and/or actin-cytoskeleton dynamics (Dergai et al., 2010)”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Discussion
What the sources say
- Not checked yetcites Dergai et al., 2010 source
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The discovery and characterization of widespread, neural-regulated microexons in the present study thus enables a systematic investigation of new and highly conserved mechanisms controlling protein interaction networks associated with vertebrate nervous system development and neurological disorders.”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Discussion
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
In the paper
“A neural-specific microexon in Protrudin/Zfyve27 was recently shown to increase its interaction with the vesicle-associated membrane protein-associated protein (VAP), and to promote neurite outgrowth (Ohnishi et al., 2014)”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Discussion
What the sources say
- Not checked yetcites Ohnishi et al., 2014 source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“recent reports have begun to link individual microexons with neurodevelopmental disorders, including ASD (Zhu et al., 2014), schizophrenia (Ovadia and Shifman, 2011) and epilepsy (Rusconi et al., 2014)”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Discussion
What the sources say
- Not checked yetcites Zhu et al., 2014 source
- Not checked yetcites Ovadia and Shifman, 2011
- Not checked yetcites Rusconi et al., 2014
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“we have previously shown that nSR100 promotes neurite outgrowth (Calarco et al., 2009)”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Discussion
What the sources say
- Not checked yetcites Calarco et al., 2009 source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Apbb1 is an adapter protein that functions in neurite outgrowth (Cheung et al., 2014; Ikin et al., 2007) and synaptic plasticity (Sabo et al., 2003), processes that have been linked to neurological disorders including ASD (Hussman et al., 2011)”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Discussion
What the sources say
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
The paper relies on this without support.
Misregulation of alternative splicing frequently causes or contributes to human disease.
“since the misregulation of AS frequently causes or contributes to human disease, there is a pressing need to systematically define the functions of splice variants in disease contexts.”
The paper relies on this without support.
Gene prediction algorithms, high-throughput RNA sequencing analysis methods, and RNA-Seq datasets generally lack the sensitivity and/or depth required to detect specific types of alternative splicing.
“Gene prediction algorithms, high-throughput RNA sequencing (RNA-Seq) analysis methods, and RNA-Seq datasets generally lack the sensitivity and/or depth required to detect specific types of AS.”
The paper relies on this without support.
It is generally not known which disease-misregulated alternative splicing events cause or contribute to disease phenotypes.
“As is the case with assessing the normal functions of AS, it is generally not known which disease-misregulated AS events cause or contribute to disease phenotypes.”
The paper relies on this without support.
Several genes with misregulated microexons have been linked to learning or intellectual disability.
“Other genes with misregulated microexons have been linked to learning or intellectual disability (e.g. APBB1, TRAPPC9, RAB3GAP1)”
The paper relies on this without support.
The ASD and control brain samples analyzed are representative of the broader ASD and control populations.
“We analyzed 24 autistic individuals and 24 controls matched by age and gender.”
The paper relies on this without support.
nSR100 mRNA expression levels reflect nSR100 protein activity or functional nSR100 levels.
“nSR100 mRNA expression is, on average, significantly downregulated in the brains of the analyzed ASD versus control subjects”
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?
In the citing paper
“the known positive correlation between SRRM4 and RBFOX1 and anticorrelation between PTBP1 and SRRM4 (refs 14,19)”
From Genome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism (2016) · cites this paper as [14]
In the citing paper
“Previous studies have identified alterations in local splicing events in ASD (19, 30) and in smaller cohorts in SCZ (2, 24) and BD (31).”
From Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder (2018) · cites this paper as [30]
In the citing paper
“several studies have demonstrated that genes carrying microexons are preferentially expressed in brain and their splicing is dysregulated in ASD (30, 82, 83).”
From Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder (2018) · cites this paper as [30]
In the citing paper
“nSR100 controls alternative splicing of 3–15 nucleotide “microexons,” which in turn alters protein-protein interactions, during neurogenesis. Reduced levels of nSR100 and dysregulated neuronal microexons are implicated in some cases of autism (Irimia et al., 2014).”
From Genetic Changes Shaping the Human Brain (2015) · cites this paper as Irimia et al., 2014
In the citing paper
“Recent studies have highlighted the importance of aberrant alternative splicing of mRNA in the brains of subjects with an ASD diagnosis (Corominas et al., 2014; Gandal et al., 2018; Irimia et al., 2014; Parikshak et al., 2016; Voineagu et al., 2011).”
From Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice (2019) · cites this paper as Irimia et al., 2014
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
“126 of 504 (30%) detected alternative microexons display a mean ΔPSI > 10 between ASD and control subjects”
§ A highly conserved program of neuronal microexons is misregulated in autistic brains > Results > Microexons are misregulated in individuals with Autism Spectrum Disorder
Reported 30 · recomputed 25
Citations
Cites
Cytoscape: A software Environment for integrated models of biomolecular interaction networks
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“3 (Shannon et al., 2003) with the following parameters: pvalue cut-off = 0.”
BackgroundSystematic and integrative analysis of large gene lists using DAVID bioinformatics resources
Huang, D. W., Sherman, B. T., & Lempicki, R. A. (2009) · Nature Protocols · doi:10.1038/nprot.2008.211 · Cited by 35,890
Ultrafast and memory-efficient alignment of short DNA sequences to the human genome.
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“These 50-nt split reads were then mapped to the corresponding genome assemblies using Bowtie (Langmead et al., 2009), using –m 1 –v 2 parameters (unique mapping with no more than two mismatches).”
MethodHTSeq—a Python framework to work with high-throughput sequencing data
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“For gene-level differential expression analysis, reads were aligned to the human genome (hg19) with TopHat2 (Kim et al., 2013) and quantified with HT-seq Counts using a union-exon model from Gencode v18 (Anders et al.”
MethodKrogh, A., Larsson, B., von Heijne, G., & Sonnhammer, E. L. L. (2001) · Journal of Molecular Biology · doi:10.1006/jmbi.2000.4315 · Cited by 12,654 · cited 1×
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BackgroundSmyth, G. K. (2004) · Statistical Applications in Genetics and Molecular Biology · doi:10.2202/1544-6115.1027 · Cited by 11,829 · cited 1×
“the empirical Bayes log-odds of differential PSI/PSU/PIRs (Smyth, 2004) (as implemented in “ebayes”, from the limma package in R).”
MethodSignalP 4.0: discriminating signal peptides from transmembrane regions
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Pfam: the protein families database
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Cited by
Sorted by citations
GENCODE reference annotation for the human and mouse genomes
Frankish, A., Diekhans, M., Ferreira, A.-M., Johnson, R., Jungreis, I., Loveland, J. E., Mudge, J. M., Sisu, C., Wright, J. C., Armstrong, J. C., et al. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky955 · Cited by 3,006
“We have also completed an effort to capture all recently described unannotated microexons (18) into GENCODE, and further added an additional 146 novel microexons mined from public SLRseq data (19).”
BackgroundPredicting splicing from primary sequence with deep learning
Jaganathan, K., Kyriazopoulou Panagiotopoulou, S., McRae, J. F., Darbandi, S. F., Knowles, D., Li, Y. I., Kosmicki, J. A., Arbelaez, J., Cui, W., Schwartz, G. B., et al. (2019) · Cell · doi:10.1016/j.cell.2018.12.015 · Cited by 2,853
“…Arises from Weak Cryptic Splice Variants Alternative splicing is a major mode of gene regulation that serves to increase the diversity of transcripts in different tissues and developmental stages, and its dysregulation is associated with disease processes (Irimia et al., 2014; Wang et al., 2008).”
BackgroundAlternative splicing as a regulator of development and tissue identity
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Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder
Gandal, M. J., Zhang, P., Hadjimichael, E., Walker, R. L., Chen, C., Liu, S., Won, H., van Bakel, H., Varghese, M., Wang, Y., et al. (2018) · Science · doi:10.1126/science.aat8127 · Cited by 1,247
“Finally, several studies have demonstrated that genes carrying microexons are preferentially expressed in the brain and their splicing is dysregulated in ASD (30, 82, 83).”
Self-citation
Metadata
- Authors
- Irimia, M., Weatheritt, R. J., Ellis, J. D., Parikshak, N. N., Gonatopoulos-Pournatzis, T., Babor, M., Quesnel-Vallières, M., Tapial, J., Raj, B., O’Hanlon, D., Barrios-Rodiles, M., Sternberg, M. J. E., Cordes, S. P., Roth, F. P., Wrana, J. L., Geschwind, D. H., & Blencowe, B. J.
- Affiliations
- University of Toronto (CA)
- MRC Laboratory of Molecular Biology (GB)
- University of California, Los Angeles (US)
- Centre for Genomic Regulation (ES)
- Imperial College London (GB)
- Mount Sinai Hospital (CA)
- Canadian Institute for Advanced Research (CA)
- Corresponding author
- Irimia, Manuel
- Blencowe, Benjamin J.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2014-12
- Volume
- 159
- Issue
- 7
- Pages
- 1511-1523
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4390143
- OpenAlex
- W2139480055
- Semantic Scholar
- 50b56e7b67ca01c7c25009821818d9e4a479c378
- Cited by
- 693
- References
- 117
- Citations by year
- 2026: 59 · 2025: 63 · 2024: 64 · 2023: 62 · 2022: 59 · 2021: 87 · 2020: 69 · 2019: 49 · 2018: 56 · 2017: 47 · 2016: 40 · 2015: 32 · 2014: 4
- FWCI
- 16.82
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institutes of Health (5r01mh094714-04)
- Canadian Institutes of Health Research
- National Institute of Mental Health (5R01MH094714, R01-MH094714, F30MH099886, R37MH060233)
- National Human Genome Research Institute (U01HG001715, R01HG003224, P50HG004233)
- National Institute of General Medical Sciences (T32GM008042)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- microexons, alternative splicing, autism spectrum disorder, SRRM4, neurogenesis, protein-protein interaction domains, evolutionary conservation, brain transcriptome
- MeSH terms
- Animals, Child Development Disorders, Pervasive, Humans, Models, Molecular, Nerve Tissue Proteins, Neurons, Temporal Lobe, Alternative Splicing, Sequence Analysis, RNA, Mice, Protein Interaction Domains and Motifs, Neurogenesis
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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