The DOI matches its Crossref record; 44 of the 44 references it cites were found in a registry or an index.
A Global Regulatory Mechanism for Activating an Exon Network Required for Neurogenesis
Open accessAbstract
The vertebrate and neural-specific Ser/Arg (SR)-related protein nSR100/SRRM4 regulates an extensive program of alternative splicing with critical roles in nervous system development. However, the mechanism by which nSR100 controls its target exons is poorly understood. We demonstrate that nSR100-dependent neural exons are associated with a unique configuration of intronic cis-elements that promote rapid switch-like regulation during neurogenesis. A key feature of this configuration is the insertion of specialized intronic enhancers between polypyrimidine tracts and acceptor sites that bind nSR100 to potently activate exon inclusion in neural cells while weakening 3' splice site recognition and contributing to exon skipping in nonneural cells. nSR100 further operates by forming multiple interactions with early spliceosome components bound proximal to 3' splice sites. These multifaceted interactions achieve dominance over neural exon silencing mediated by the splicing regulator PTBP1. The results thus illuminate a widespread mechanism by which a critical neural exon network is activated during neurogenesis.
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In the citing paper
“Previous experimental perturbation of three splicing factors, Rbfox1 (ref. 18), SRRM4 (ref. 19), and PTBP1 (ref. 20), shows strong overlap with the differential splicing changes found in ASD cortex, further supporting these predicted relationships (Fig. 1h, Extended Data Fig. 5b).”
From Genome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism (2016) · cites this paper as [19]
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 [19]
In the citing 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).”
From A Highly Conserved Program of Neuronal Microexons Is Misregulated in Autistic Brains (2014) · cites this paper as Raj et al., 2014
In the citing paper
“SRRM4 frequently binds UGC-rich sequences located between the polypyrimidine tract and the 3′ splice site of target exons30.”
From The neurogenetics of alternative splicing (2016) · cites this paper as [30]
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Citations
Cites
Transcriptome-wide Identification of RNA-Binding Protein and MicroRNA Target Sites by PAR-CLIP
Hafner, M., Landthaler, M., Burger, L., Khorshid, M., Hausser, J., Berninger, P., Rothballer, A., Ascano, M., Jungkamp, A.-C., Munschauer, M., et al. (2010) · Cell · doi:10.1016/j.cell.2010.03.009 · Cited by 2,873 · cited 1×
“nSR100 Binds Intronic UGC Motifs Adjacent to the 30 Splice Site of Target Exons In Vivo To investigate whether nSR100 binds to the UGC, C/U-rich, and/ or other motifs, we used PAR-iCLIP, which employs incorporation of the photoreactive nucleoside analog 4-thiouridine in nascent RNA to increase crosslinking efficiency…”
MethodExpansion of the eukaryotic proteome by alternative splicing
Nilsen, T. W., & Graveley, B. R. (2010) · Nature · doi:10.1038/nature08909 · Cited by 2,254
Maximum Entropy Modeling of Short Sequence Motifs with Applications to RNA Splicing Signals
Yeo, G. W.-M., & Burge, C. B. (2004) · Journal of Computational Biology · doi:10.1089/1066527041410418 · Cited by 2,042
Makeyev, E. V., Zhang, J., Carrasco, M. A., & Maniatis, T. (2007) · Molecular Cell · doi:10.1016/j.molcel.2007.07.015 · Cited by 1,395 · cited 3×
“, 2009), which is thought to contribute to neural exon inclusion (Makeyev et al., 2007; Zheng et al., 2012), Ptbp2 expression is not sufficient for the activation of nSR100 target exons.”
BackgroundHITS-CLIP yields genome-wide insights into brain alternative RNA processing
Licatalosi, D. D., Mele, A., Fak, J. J., Ule, J., Kayikci, M., Chi, S. W., Clark, T. A., Schweitzer, A. C., Blume, J. E., Wang, X., et al. (2008) · Nature · doi:10.1038/nature07488 · Cited by 1,352 · cited 2×
“We generated a merged in vivo binding map (Licatalosi et al., 2008) displaying the mean, normalized distributions of nSR100 293T cell PARiCLIP crosslink sites within 400 nt windows surrounding the 157 conserved target exons, and a set of 400 control exons that are not nSR100 targets but that have a comparable PSI dist…”
BackgroundMethodSelf-citationThe Evolutionary Landscape of Alternative Splicing in Vertebrate Species
Barbosa-Morais, N. L., Irimia, M., Pan, Q., Xiong, H. Y., Gueroussov, S., Lee, L. J., Slobodeniuc, V., Kutter, C., Watt, S., Çolak, R., et al. (2012) · Science · doi:10.1126/science.1230612 · Cited by 1,063
Self-citationEvolutionary Dynamics of Gene and Isoform Regulation in Mammalian Tissues
Merkin, J., Russell, C., Chen, P., & Burge, C. B. (2012) · Science · doi:10.1126/science.1228186 · Cited by 972 · cited 1×
“vertebrate nervous system, which possesses among the most complex yet highly conserved repertoires of regulated AS events (Barbosa-Morais et al., 2012; Merkin et al., 2012).”
BackgroundRNA processing and its regulation: global insights into biological networks
Licatalosi, D. D., & Darnell, R. B. (2009) · Nature Reviews Genetics · doi:10.1038/nrg2673 · Cited by 777 · cited 1×
“Transcriptome-wideprofilinghasuncovered vast repertoires of splice variants in metazoan species, many of which are highly conserved and regulated in a cell- and tissuespecific manner (Irimia and Blencowe, 2012; Licatalosi and Darnell, 2010; Nilsen andGraveley, 2010).”
BackgroundBoutz, P. L., Stoilov, P., Li, Q., Lin, C.-H., Chawla, G., Ostrow, K., Shiue, L., Ares, M., & Black, D. L. (2007) · Genes & Development · doi:10.1101/gad.1558107 · Cited by 577 · cited 3×
“Consistent with reports showing that Ptbp1 primarily functions to repress exon splicing (Boutz et al., 2007; Han et al., 2014; Llorian et al., 2010), knockdown of Ptbp1”
BackgroundCloning and domain structure of the mammalian splicing factor U2AF
Zamore, P. D., Patton, J. G., & Green, M. R. (1992) · Nature · doi:10.1038/355609a0 · Cited by 568 · cited 1×
“Among the detected nSR100 interaction partners are the two subunits of the U2 snRNP auxiliary splicing factor, U2AF65/ U2AF2 and U2AF35/U2AF1, which bind directly to the polypyrimidine tract and 30 splice site AG dinucleotide, respectively (Merendino et al., 1999; Wu et al., 1999; Zamore et al., 1992; Zorio and Blumen…”
Background
Cited by
Sorted by citations
Alternative splicing as a regulator of development and tissue identity
Baralle, F. E., & Giudice, J. (2017) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2017.27 · Cited by 1,333
Human Gut Microbiota from Autism Spectrum Disorder Promote Behavioral Symptoms in Mice
Sharon, G., Cruz, N. J., Kang, D.-W., Gandal, M. J., Wang, B., Kim, Y.-M., Zink, E. M., Casey, C. P., Taylor, B. C., Lane, C. J., et al. (2019) · Cell · doi:10.1016/j.cell.2019.05.004 · Cited by 1,182
“…whether oASD brains exhibited differential patterns of alternative splicing (AS), a feature found in human ASD brains (Gandal et al., 2018; Irimia et al., 2014; Parikshak et al., 2016; Parras et al., 2018). rMATS analysis (Shen et al., 2014) identified 560 genes that showed different AS…”
BackgroundInfluentialAlternative Splicing Regulatory Networks: Functions, Mechanisms, and Evolution
Ule, J., & Blencowe, B. J. (2019) · Molecular Cell · doi:10.1016/j.molcel.2019.09.017 · Cited by 780
“It is intriguing that RNPS1, an auxiliary EJC component, can repress inclusion of such cryptic microexons, whereas, on the other hand, it promotes splicing of canonical neural microexons (Gonatopoulos-Pournatzis et al., 2018).”
BackgroundInfluentialSelf-citationA Highly Conserved Program of Neuronal Microexons Is Misregulated in Autistic Brains
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., et al. (2014) · Cell · doi:10.1016/j.cell.2014.11.035 · Cited by 693
“, 2013)), or overexpression (nSR100 in human 293T cells (Raj et al., 2014)), and their associated controls, to identify AS exons and microexons whose inclusion levels are affected by experimental manipulation of the expression of the splicing factors.”
InfluentialSelf-citationGenome-wide changes in lncRNA, splicing, and regional gene expression patterns in autism
Parikshak, N. N., Swarup, V., Belgard, T. G., Irimia, M., Ramaswami, G., Gandal, M. J., Hartl, C., Leppa, V., Ubieta, L. D. L. T., Huang, J., et al. (2016) · Nature · doi:10.1038/nature20612 · Cited by 685
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Metadata
- Authors
- Raj, B., Irimia, M., Braunschweig, U., Sterne-Weiler, T., O’Hanlon, D., Lin, Z.-Y., Chen, G. I., Easton, L. E., Ule, J., Gingras, A.-C., Eyras, E., & Blencowe, B. J.
- Affiliations
- University of Toronto (CA)
- Mount Sinai Hospital (CA)
- MRC Laboratory of Molecular Biology (GB)
- Institució Catalana de Recerca i Estudis Avançats (ES)
- Corresponding author
- Blencowe, Benjamin J.
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2014-10
- Volume
- 56
- Issue
- 1
- Pages
- 90-103
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC4608043
- OpenAlex
- W2009302210
- Cited by
- 132
- References
- 44
- Citations by year
- 2026: 4 · 2025: 12 · 2024: 11 · 2023: 10 · 2022: 12 · 2021: 4 · 2020: 10 · 2019: 14 · 2018: 15 · 2017: 10 · 2016: 14 · 2015: 11 · 2014: 5
- FWCI
- 5.46
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- ANU Open Research (Australian National University) (submittedVersion)
- Funders
- Wellcome Trust (089701)
- Canadian Institutes of Health Research
- 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 › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- SRRM4, alternative splicing, neurogenesis, intronic enhancer, polypyrimidine tract, 3' splice site recognition, exon skipping, exon inclusion, spliceosome, PTBP1, cis-regulatory elements, splicing regulation
- MeSH terms
- Animals, Cell Differentiation, Cell Line, Exons, Gene Expression Regulation, Humans, Models, Genetic, Nerve Tissue Proteins, Alternative Splicing, Mice, Neurogenesis, HEK293 Cells, Nucleotide Motifs
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