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
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“, 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…”
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Items 101–132 of 132
Sehgal, P. D., Naqvi, A. S., Higgins, M., Liu, J., Harvey, K., Jarroux, J., Kim, T. W., Mankaliye, B., Mishra, P., Watterson, G., et al. (2025) · Cell Reports · doi:10.1016/j.celrep.2025.116099 · Cited by 6
Current advances of targeting epigenetic modifications in neuroendocrine prostate cancer
Cheng, W., & Wang, H. (2021) · Tzu Chi Medical Journal · doi:10.4103/tcmj.tcmj_220_20 · Cited by 6
“This paradox can be explained by the overexpression of SRRM4 (serine/arginine repetitive matrix protein 4), which promotes the formation of truncated REST lacking the transcriptional repressor domain [76].”
BackgroundBonnal, S., Bajew, S., Martinez-Corral, R., & Irimia, M. (2025) · Nature Structural & Molecular Biology · doi:10.1038/s41594-025-01634-1 · Cited by 5
Self-citationBuonerba, C., Lorenzo, G. D., & Sonpavde, G. (2016) · Expert Review of Molecular Diagnostics · doi:10.1080/14737159.2016.1240031 · Cited by 5
“SRRM4 is a RNA splicing factor that serves as a master regulator of neural-specific exon networks and is required by embryonic stem cells in order to transdifferentiate into neural cells [50,51].”
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Parikshak, N., Swarup, V., Belgard, T. G., Gandal, M. J., Irimia, M., Leppä, V., Lowe, J. K., Johnson, R., Blencowe, B. J., Horvath, S., et al. (2016) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/077057 · Cited by 4
Self-citationPillai, V. S., Ravindran, S., Krishna, G., Abhinand, C. S., Sathi, S. N., & Veettil, M. V. (2025) · Viruses · doi:10.3390/v17020234 · Cited by 3
“Conversely, in non-neuronal cells, REST in turn represses nSR100, thereby ensuring the repression of neuronal genes (Figure A1B) [35,73].”
dSreg: a Bayesian model to integrate changes in splicing and RNA-binding protein activity
Martí‐Gómez, C., Lara‐Pezzi, E., & Sánchez‐Cabo, F. (2019) · Bioinformatics · doi:10.1093/bioinformatics/btz915 · Cited by 3
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Tracks through the genome to physiological events
Lipscombe, D., Pan, J. Q., & Schorge, S. (2015) · Experimental Physiology · doi:10.1113/ep085129 · Cited by 3
“…in insects; muscle fibre type specification; synaptic scaling; cell signalling; pluripotent stem cell renewal; and, possibly, speciation (Aoto et al. 2013; Han et al. 2013; Jepson et al. 2013; Lipscombe et al. 2013a; Venables et al. 2013; Lah et al. 2014; Raj et al. 2014; Lu et al. 2014).”
BackgroundThe Role of mRNA Alternative Processing in Mammalian Neurodevelopment
Liu, X., Zuo, J. J., Zhang, G., Han, X., & Tian, Y. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms262211075 · Cited by 3
“In mammalian cell culture and zebrafish models, SRRM4 has been shown to be required for neurogenesis and neuronal differentiation [54,55].”
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The origin of neural microexons
Faraway, R., & Ule, J. (2019) · Nature Ecology & Evolution · doi:10.1038/s41559-019-0818-1 · Cited by 2
Self-citationProfound Associations between Maternal Infectious Disease and Fetal Neurodevelopmental DelaysPreprint
Carp, T.-N., & Metoudi, M. (2022) · Preprints.org · doi:10.20944/preprints202212.0190.v1 · Cited by 1
Carp, T.-N. (2024) · Preprints.org · doi:10.20944/preprints202401.2108.v1 · Cited by 2
Boosting Macroevolution: Genomic Changes Triggering Qualitative Expansions of Regulatory Potential
Irimia, M., & Maeso, I. (2019) · Fascinating life sciences · doi:10.1007/978-3-030-18202-1_9 · Cited by 1
Self-citationTsao, W., Huang, Y.-C., Sung, H.-H., Lin, C., Hsu, H., Lin, H., & Chien, C. (2025) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-025-05860-0 · Cited by 1
“Additionally, SR-related protein of 100 kDa (nSR100/ Srrm4) interacts with various proteins, including Sf3b1, to regulate exon inclusion, thereby impacting neurogenesis and neuritogenesis [19, 20].”
Harrer, P., Kittke, V., Saparov, A., Knaus, A., Zeidler, S., Schot, R., Kraft, F., Begemann, M., Koudijs, S. M., Sorrentino, U., et al. (2026) · Movement Disorders · doi:10.1002/mds.70297 · Cited by 1
“For a comprehensive list of previously determined SRRM4 -dependent genes, see Raj et al 10 and Cap-poni et al, 11 and for their associations to monogenic disorders, see the OMIM database.”
InfluentialPan, Y., Liu, B., & Pei, D. (2022) · DNA and Cell Biology · doi:10.1089/dna.2022.0322 · Cited by 1
“For example, a compound of SR proteins SR100 and SRRM4 binds to ISE upstream of the 3 ¢ splice site rather than ESE in microexons, thus exerting the opposite AS function (Chen and Manley, 2009; Raj et al. , 2014).”
Shirakawa, Y., Li, H., Inoue, Y., Izumi, H., Kaga, Y., Goto, Y., Inoue, K., & Inagaki, M. (2023) · IBRO Neuroscience Reports · doi:10.1016/j.ibneur.2023.12.005 · Cited by 1
“Afterward, Srrm4 expression decreases as neuronal maturation occurs (Raj et al., 2014).”
BackgroundDevelopmental and cell-specific expression of Cacna1d splice variantsPreprint
LaCarubba, B., Bunda, A., Savage, K. R., Hannah, S. S., Akiki, M., Thomas, F., & Andrade, A. (2019) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/598722 · Cited by 1
“As a result, the expression of splice variants is substantially different between newborns and adults, as well as among cellular sub-populations (Calarco et al., 2009; Grabowski, 2011; Fogel et al., 2012; Raj et al., 2014).”
BackgroundYang, Y. A., Lee, G. C., Nakagaki-Silva, E. E., Huang, Y., Peacey, M., Partridge, R., Gooding, C., & Smith, C. W. J. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.01.23.525191 · Cited by 1
“For example, many neuron-specific exons are included as a result of reduced repression by PTBP1 combined with increased activation by RBFOX or SRRM3 proteins (Barash et al., 2010, Castle et al., 2008, Raj et al., 2014, Wang et al., 2008).”
BackgroundMaretty, L., Sibbesen, J. A., & Krogh, A. (2014)
Functional Consequences of Embryonic Stem Cell- Specific Alternative Splicing
Nachman, E. N. (2015) · TSpace (University of Toronto)
Large-scale study of rna processing alterations in multiple cancers
Singh, B. (2017) · LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas)
Lee, A. R. (2019) · cIRcle (University of British Columbia) · doi:10.14288/1.0378323
“Furthermore, SRRM4 expression, though high in the brain during embryonic development of the neural system, decreases in adult tissues and is rarely detected in non-neuronal cells (95,98,100).”
BackgroundMethodInfluentialJuan‐Mateu, J., Bajew, S., Miret-Cuesta, M., Iñiguez, L., López-Pascual, A., Bonnal, S., Atla, G., Bonàs‐Guarch, S., Ferrer, J. P., Valcárcel, J., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.04.02.486809
Self-citationEssential Role of nSR100 and CPEB4 Proteins During the Development of the Nervous System
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CCAR1 promotes DNA repair via an unanticipated role in alternative splicingPreprint
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Specific RNA transcripts (SRTs): From concepts to the clinic
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“[36] This regulation is crucial for neuronal differentiation, and disruptions in SRRM4 function have been linked to autism spectrum disorders (ASDs).”
Alternative splicing regulates PACC1 function and promotes acidosis-induced cytotoxicity
Tamburro, S., Gorrieri, G., Callegari, N., Guida, F., Antonini, F., Musante, I., Baldassari, S., Zara, F., & Scudieri, P. (2026) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2025.1754079
“Alternative splicing is a fundamental mechanism of proteomic diversification, particularly in the brain, where it regulates neurodevelopment, cell-type identity, and synaptic function (Raj et al., 2014; Raj and Blencowe, 2015; Vuong et al., 2016; Furlanis and Scheiffele, 2018).”
The cellular landscape of druggable RNA-binding proteins
Timoteo, G. D., George, B. M., Abdel-Wahab, O. I., Flynn, R. A., & Tzelepis, K. (2026) · Nature Reviews Drug Discovery · doi:10.1038/s41573-026-01531-2
A microexon regulatory code reveals autism-linked genetic variation
Parada, G. E., Bretschneider, H., Li, J. D., Fine, J. L., Dupas, S. J., Ellis, J. D., Braunschweig, U., Bonnal, S., Dalal, T., Engchuan, W., et al. (2026) · Nature · doi:10.1038/s41586-026-11119-w
Self-citation
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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