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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
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“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
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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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“4d-4f), in concordance with the described role of CELF , RBFOX and SRRM4 genes in neuronal differentiation (Kim et al., 2013b; Li et al., 2015; Norris et al., 2014; Raj et al., 2014).”
BackgroundSelf-citationRaj, B., & Blencowe, B. J. (2015) · Neuron · doi:10.1016/j.neuron.2015.05.004 · Cited by 475
“Nova double knockout mice are paralyzed and die immediately after birth (Ruggiu et al., 2009).”
BackgroundSelf-citationCellular plasticity and the neuroendocrine phenotype in prostate cancer
Davies, A. H., Beltran, H., & Zoubeidi, A. (2018) · Nature Reviews Urology · doi:10.1038/nrurol.2018.22 · Cited by 431
Tapial, J., Ha, K., Sterne-Weiler, T., Gohr, A., Braunschweig, U., Hermoso, A., Quesnel-Vallières, M., Permanyer, J., Sodaei, R., Márquez, Y., et al. (2017) · Genome Research · doi:10.1101/gr.220962.117 · Cited by 441
“…of inclusion levels that have been validated at a high rate by RT-PCR assays (Han et al. 2013; Braunschweig et al. 2014; Irimia et al. 2014; Raj et al. 2014; Giampietro et al. 2015; Gueroussov et al. 2015; Quesnel-Vallières et al. 2015, 2016; Solana et al. 2016) (and see below, “ Neural…”
Self-citationThe neurogenetics of alternative splicing
Vuong, C. K., Black, D. L., & Zheng, S. (2016) · Nature Reviews Neuroscience · doi:10.1038/nrn.2016.27 · Cited by 340
Leveraging transcript quantification for fast computation of alternative splicing profiles
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“…validation using PCR methods and the characterization of regulatory mechanisms using sequence analysis and biochemical approaches (Bechara et al. 2013, Raj et al. 2014); and they provide a valuable description for predictive and therapeutic strategies (Xiong et al. 2014, Hua et al. 2015).”
BackgroundMethodInfluentialSelf-citationGenetic Control of Expression and Splicing in Developing Human Brain Informs Disease Mechanisms
Walker, R. L., Ramaswami, G., Hartl, C., Mancuso, N., Gandal, M. J., de la Torre-Ubieta, L., Paşaniuc, B., Stein, J. L., & Geschwind, D. H. (2019) · Cell · doi:10.1016/j.cell.2019.09.021 · Cited by 262
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“To experimentally validate Whippet-derived predictions of high AS-event entropy, RNA-seq data (Raj et al., 2014) from mouse neuroblastoma (N2a) cells were analyzed and 10 events with different predicted degrees of entropy and complexity involving tandem arrays of alternative exons were tested by RT-PCR (STAR Methods).”
MethodSelf-citationEpigenetic modulations and lineage plasticity in advanced prostate cancer
Ge, R., Wang, Z., Montironi, R., Jiang, Z., Cheng, M., Santoni, M., Huang, K., Massari, F., Lü, X., Cimadamore, A., et al. (2020) · Annals of Oncology · doi:10.1016/j.annonc.2020.02.002 · Cited by 215
Antagonistic regulation of mRNA expression and splicing by CELF and MBNL proteinsPreprint
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Quesnel-Vallières, M., Dargaei, Z., Irimia, M., Gonatopoulos-Pournatzis, T., Ip, J. Y., Wu, M., Sterne-Weiler, T., Nakagawa, S., Woodin, M. A., Blencowe, B. J., et al. (2016) · Molecular Cell · doi:10.1016/j.molcel.2016.11.033 · Cited by 178
“Moreover, UGC motifs, which represent binding sites through which nSR100 promotes neural exon inclusion (Nakano et al., 2012; Raj et al., 2014), are significantly enriched immediately upstream of microexons, as well as of longer cassette exons that display increased skipping after neuronal…”
BackgroundMethodSelf-citationMultilayered Control of Alternative Splicing Regulatory Networks by Transcription Factors
Han, H. R., Braunschweig, U., Gonatopoulos-Pournatzis, T., Weatheritt, R. J., Hirsch, C. L., Ha, K., Radovani, E., Nabeel‐Shah, S., Sterne‐Weiler, T., Wang, J., et al. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.01.011 · Cited by 182
Self-citationLi, Y., Donmez, N., Şahinalp, S. C., Xie, N., Wang, Y., Xue, H., Mo, F., Beltran, H., Gleave, M. E., Wang, Y. Z., et al. (2016) · European Urology · doi:10.1016/j.eururo.2016.04.028 · Cited by 177
“SRRM4 is a master regulator of neural-specific exon networks required for embryonic stem cells to transdifferentiate into neural cells [12,15].”
Regulation of Neuronal Differentiation, Function, and Plasticity by Alternative Splicing
Furlanis, E., & Scheiffele, P. (2018) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev-cellbio-100617-062826 · Cited by 176
“Splicing factors frequently act synergistically on a single splice site, like in the case of Nova and Rbfox (Li et al., 2015b; Zhang et al., 2010), or antagonistically like nSR100 and Ptbp1 (Raj et al., 2014).”
BackgroundIntron retention and nuclear loss of SFPQ are molecular hallmarks of ALS
Luisier, R., Tyzack, G. E., Hall, C. E., Mitchell, J. S., Devine, H. E., Taha, D. M., Malik, B. A., Meyer, I., Greensmith, L., Newcombe, J., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-04373-8 · Cited by 164
Self-citationEssential roles for the splicing regulator nSR100/SRRM4 during nervous system development
Quesnel-Vallières, M., Irimia, M., Cordes, S. P., & Blencowe, B. J. (2015) · Genes & Development · doi:10.1101/gad.256115.114 · Cited by 155
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An alternative splicing event amplifies evolutionary differences between vertebrates
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Self-citationGonatopoulos-Pournatzis, T., Aregger, M., Brown, K. R., Farhangmehr, S., Braunschweig, U., Ward, H. N., Ha, K. C. H., Weiss, A., Billmann, M., Durbic, T., et al. (2020) · Nature Biotechnology · doi:10.1038/s41587-020-0437-z · Cited by 142
Self-citationPTBP1 and PTBP2 Serve Both Specific and Redundant Functions in Neuronal Pre-mRNA Splicing
Vuong, J. K., Lin, C.-H., Zhang, M., Chen, L., Black, D. L., & Zheng, S. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.11.034 · Cited by 143
“One possibility for the latter is NSR100, which has been shown to antagonize PTBP1 on certain exons, but whose expression more closely aligns with PTBP2 during development (Raj et al., 2014).”
BackgroundAlternative splicing: the pledge, the turn, and the prestige
Gallego-Paez, L. M., Bordone, M. C., Leote, A. C., Saraiva-Agostinho, N., Ascensão-Ferreira, M., & Barbosa‐Morais, N. L. (2017) · Human Genetics · doi:10.1007/s00439-017-1790-y · Cited by 143
RNA splicing analysis using heterogeneous and large RNA-seq datasets
Vaquero-Garcia, J., Aicher, J. K., Jewell, S., Gazzara, M. R., Radens, C. M., Jha, A., Green, C. J., Norton, S., Lahens, N. F., Grant, G. R., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-36585-y · Cited by 129
“In addition to SRRM4 and SRSF11, the RBFOX family is highly expressed in neuronal tissues and is known to enhance exon inclusion when it binds downstream of the 5 ’ ss 27,28 .”
BackgroundInfluentialGonatopoulos-Pournatzis, T., Wu, M., Braunschweig, U., Roth, J. F., Han, H. R., Best, A. J., Raj, B., Aregger, M., O’Hanlon, D., Ellis, J. D., et al. (2018) · Molecular Cell · doi:10.1016/j.molcel.2018.10.008 · Cited by 122
“The AP-MS and Bio-ID data show that Srrm4-interacting and proximal proteins are highly enriched in components that function in the formation of complexes associated with pre-mRNA processing, extending our previous analysis (Raj et al., 2014).”
BackgroundResultInfluentialSelf-citationGonatopoulos-Pournatzis, T., Niibori, R., Salter, E. W., Weatheritt, R. J., Tsang, B., Farhangmehr, S., Liang, X., Braunschweig, U., Roth, J. F., Zhang, S., et al. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.01.006 · Cited by 120
“Srrm4, Srrm3, and Srsf11, but not GFP (analyzed as a negative control), form binding peaks proximally upstream of both microexons, supporting a direct role in their regulation (Figures 2C, 2D, S2D, and S2E; Gonatopoulos-Pournatzis et al., 2018; Irimia et al., 2014; Raj et al., 2014).”
BackgroundSelf-citationRNA-binding proteins balance brain function in health and disease
Schieweck, R., Ninkovic, J., & Kiebler, M. A. (2020) · Physiological Reviews · doi:10.1152/physrev.00047.2019 · Cited by 111
Neurodegenerative diseases: a hotbed for splicing defects and the potential therapies
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“Several SRRM4-regulated micro-exons have demonstrated high levels of inclusion during neuronal maturation, which is directly correlated to the high levels of SRRM4 [58, 60, 61].”
BackgroundInfluentialA novel protein domain in an ancestral splicing factor drove the evolution of neural microexons
Torres-Méndez, A., Bonnal, S., Márquez, Y., Roth, J. F., Iglesias, M., Permanyer, J., Almudí, I., O’Hanlon, D., Guitart, T., Soller, M., et al. (2019) · Nature Ecology & Evolution · doi:10.1038/s41559-019-0813-6 · Cited by 93
Self-citationDevelopmental isoform diversity in the human neocortex informs neuropsychiatric risk mechanisms
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“nSR100 increases expression of nPTB and works cooperatively with nPTB to overcome PTB-mediated repression during neuronal differentiation and consequently promote neural-specific exon splicing (Calarco et al., 2009; Raj et al., 2014).”
BackgroundInfluentialMicroexons: at the nexus of nervous system development, behaviour and autism spectrum disorder
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“These and subsequent studies revealed that SRRM4 has the greatest impact on microexons; it activates more than half of all neural microexons, through binding UGC-containing motifs located between the 30 splice site and polypyrimidine tract [5,16,17].”
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Defects in the Alternative Splicing-Dependent Regulation of REST Cause Deafness
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The Long Noncoding RNA Pnky Is a Trans-acting Regulator of Cortical Development In Vivo
Andersen, R., Hong, S. J., Lim, J. J., Cui, M., Harpur, B. A., Hwang, E. E., Delgado, R. N., Ramos, A. D., Liu, S. J., Blencowe, B. J., et al. (2019) · Developmental Cell · doi:10.1016/j.devcel.2019.04.032 · Cited by 65
“We also compared the splicing changes that occur upon loss of Pnky with two previously-generated datasets of PTBP1 KD in different neural cells (Raj et al., 2014; Ramos et al., 2015).”
MethodResultSelf-citationMallory, M. J., Allon, S. J., Qiu, J., Gazzara, M. R., Tapescu, I., Martínez, N. M., Fu, X., & Lynch, K. W. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1423695112 · Cited by 67
“Therefore, regulation of the level of a particular splicing regulatory protein can impact the expression pattern of hundreds of genes, as had been demonstrated in numerous knock-down and knockout studies (4, 6, 7).”
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Tranchevent, L.-C., Aubé, F., Dulaurier, L., Benoit‐Pilven, C., Rey, A., Poret, A., Chautard, É., Mortada, H., Desmet, F.-O., Chakrama, F. Z., et al. (2017) · Genome Research · doi:10.1101/gr.212696.116 · Cited by 64
“…with the effort of the research community to characterize alternative splicing-dependent protein interaction networks (Corominas et al. 2014; Raj et al. 2014; Li et al. 2015; Tseng et al. 2015; Will and Helms 2016; Yang et al. 2016a) and with web services allowing the association of…”
Mis-splicing of a neuronal microexon promotes CPEB4 aggregation in ASD
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“On the opposite side of the length spectrum, a commonly encountered problem is the mapping of microexons , a class of exons shorter than 30 nucleotides in size that have key roles in brain development and neuropathologies 120,121 .”
Self-citationOhnishi, T., Shirane, M., & Nakayama, K. I. (2017) · Scientific Reports · doi:10.1038/srep41130 · Cited by 47
QuakingRegulatesNeurofascin 155Expression for Myelin and Axoglial Junction Maintenance
Darbelli, L., Vogel, G., Almazán, G., & Richard, S. (2016) · Journal of Neuroscience · doi:10.1523/jneurosci.3529-15.2016 · Cited by 45
Fas apoptosis inhibitory molecules: more than death‐receptor antagonists in the nervous system
Planells‐Ferrer, L., Urresti, J., Coccia, E., Galenkamp, K. M. O., Calleja‐Yagüe, I., López‐Soriano, J., Carriba, P., Barneda‐Zahonero, B., Segura, M. F., & Comella, J. X. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13729 · Cited by 40
“PTBP1 promotes neural exon skipping, while nSR100 (which is up-regulated during neuronal differentiation) induces the inclusion of neural exons (Raj et al. 2014).”
BackgroundCole, B. S., Tapescu, I., Allon, S. J., Mallory, M. J., Qiu, J., Lake, R. J., Fan, H.-Y., Fu, X., & Lynch, K. W. (2015) · RNA · doi:10.1261/rna.052969.115 · Cited by 34
“Importantly, tissue-specific differences in alternative splicing (AS) have been suggested to shape cell-fate decisions (Gehman et al. 2012; Licatalosi et al. 2012; Xue et al. 2013; Raj et al. 2014; Quesnel-Vallieres et al. 2015), while signal-induced changes in AS have been observed in response to metabolic, neuronal,…”
BackgroundFrançois, B. L., Zhang, L., Mahajan, G., Stockmeier, C. A., Friedman, E., & Albert, P. R. (2018) · Journal of Neuroscience · doi:10.1523/jneurosci.0902-18.2018 · Cited by 39
“This indicates that PTBP1, but not PTBP2, represses 5-HT1A mRNA splicing in SKN-SH cells.”
BackgroundInfluentialKaarijärvi, R., Kaljunen, H., & Ketola, K. (2021) · Cancers · doi:10.3390/cancers13040692 · Cited by 35
RNA Splicing of the BHC80 Gene Contributes to Neuroendocrine Prostate Cancer Progression
Li, Y., Xie, N., Chen, R., Lee, A. R., Lovnicki, J. M., Morrison, E. A., Fazli, L., Zhang, Q., Musselman, C. A., Wang, Y. Z., et al. (2019) · European Urology · doi:10.1016/j.eururo.2019.03.011 · Cited by 31
Alternative splicing of LSD1+8a in neuroendocrine prostate cancer is mediated by SRRM4
Coleman, D. J., Sampson, D. A., Sehrawat, A., Kumaraswamy, A., Sun, D., Wang, Y. Z., Schwartzman, J. A., Urrutia, J. A., Lee, A. R., Coleman, I. M., et al. (2020) · Neoplasia · doi:10.1016/j.neo.2020.04.002 · Cited by 29
“Following immunoprecipitation, we performed qRT-PCR using primers matching the putative UGC motif upstream of the splice acceptor site (8a 50, previously shown to be important for SRRM4-dependent splicing [18]), and the exon–intron junction of exon 8a and intron 9 (8a 30) (Fig.”
MethodFritzsch, B., Jahan, I., Pan, N., & Elliott, K. L. (2014) · Cell and Tissue Research · doi:10.1007/s00441-014-2043-1 · Cited by 29
“Another layer of complexity, related to the gene expression regulation (Davidson 2010) and differential splicing in neurosensory cells (Nakano et al. 2012; Raj et al. 2014), is beyond the scope of this review.”
Han, H. R., Best, A. J., Braunschweig, U., Mikolajewicz, N., Li, J. D., Roth, J. F., Chowdhury, F., Mantica, F., Nabeel‐Shah, S., Parada, G. E., et al. (2022) · Molecular Cell · doi:10.1016/j.molcel.2022.06.036 · Cited by 27
Self-citationScheckel, C., & Darnell, R. B. (2014) · The EMBO Journal · doi:10.15252/embj.201490651 · Cited by 26
“Recently published genome-wide RNA-binding maps for RBFOX proteins in the mouse brain suggested that 30 intronic RBFOX binding increases exon inclusion (Weyn-Vanhentenryck et al, 2014).”
BackgroundFrankowski, H., Yeboah, F., Berry, B. J., Kinoshita, C., Lee, M., Evitts, K. M., Davis, J., Kinoshita, Y., Morrison, R. S., & Young, J. E. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22052526 · Cited by 26
“Prompted by previous reports implicating the neuron-specific splicing factor SRRM4 in the alternative splicing of Endo-B1 [31,51], we examined whether changes in SRRM4 expression correlate with the appearance of Endo-B1b/c isoforms.”
BackgroundNeuronal-specific microexon splicing of TAF1 mRNA is directly regulated by SRRM4/nSR100
Capponi, S., Stöffler, N., Irimia, M., van Schaik, F. M. A., Ondik, M. M., Biniossek, M. L., Lehmann, L., Mitschke, J., Vermunt, M. W., Creyghton, M. P., et al. (2019) · RNA Biology · doi:10.1080/15476286.2019.1667214 · Cited by 25
“A previous study identified UGC-containing motifs as critical SRRM4 binding sites to promote neuronal microexon inclusion [2].”
BackgroundInfluentialSelf-citationPancreatic microexons regulate islet function and glucose homeostasis
Juan‐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. (2023) · Nature Metabolism · doi:10.1038/s42255-022-00734-2 · Cited by 25
Self-citationNeurogenesis: Regulation by Alternative Splicing and Related Posttranscriptional Processes
Lara‐Pezzi, E., Desco, M., Gatto, A., & Gómez‐Gaviro, M. V. (2016) · The Neuroscientist · doi:10.1177/1073858416678604 · Cited by 24
Lineage plasticity-mediated therapy resistance in prostate cancer
Huang, H., & Blee, A. M. (2018) · Asian Journal of Andrology · doi:10.4103/aja.aja_41_18 · Cited by 24
Han, K. A., Yoon, T.-H., Kim, J., Lee, J., Lee, J. Y., Jang, G., Um, J. W., Kim, J. K., & Ko, J. (2024) · Nature Communications · doi:10.1038/s41467-024-45695-0 · Cited by 23
“We have done so in the revised manuscript.”
Non-Canonical Splicing and Its Implications in Brain Physiology and Cancer
Pitolli, C., Marini, A., Sette, C., & Pagliarini, V. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23052811 · Cited by 23
“SRRM4 binds specialized upstream intronic enhancer elements together with the serine/arginine rich splicing factor 11 (SRSF11) and RNA binding protein with serine rich domain 1 (RNPS1) thus, to posi-tively regulate the inclusion of microexons into mature mRNAs [79,80].”
BackgroundSRRM4 Expands the Repertoire of Circular RNAs by Regulating Microexon Inclusion
Conn, V. M., Gabryelska, M., Marri, S., Stringer, B. W., Ormsby, R. J., Penn, T., Poonnoose, S. I., Kichenadasse, G., & Conn, S. J. (2020) · Cells · doi:10.3390/cells9112488 · Cited by 20
“Although there exists a number of neural-specific RNA splicing factors which affect alternative splicing, including RBFOX1, SRSF11, and PTBP1/2, most neural MEs are regulated by the Serine/arginine repetitive matrix 4 or Neural-specific serine/arginine repetitive splicing factor of 100 kDa (SRRM4/nSR100), through its…”
BackgroundEmerging Roles of RNA-Binding Proteins in Inner Ear Hair Cell Development and Regeneration
Shi, D., Cheng, X.-N., Saquet, A., & Grifone, R. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232012393 · Cited by 20
Regulation of alternative splicing and polyadenylation in neurons
Lee, S., Aubee, J. I., & Lai, E. C. (2023) · Life Science Alliance · doi:10.26508/lsa.202302000 · Cited by 21
Genome Sequencing and RNA-Motif Analysis Reveal Novel Damaging Noncoding Mutations in Human Tumors
Singh, B., Trincado, J. L., Tatlow, P., Piccolo, S., & Eyras, E. (2018) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-17-0601 · Cited by 20
Self-citationLee, A. R., Che, N., Lovnicki, J. M., & Dong, X. (2018) · Frontiers in Oncology · doi:10.3389/fonc.2018.00093 · Cited by 18
“These CRPC-NE-specific spliced genes have recognized functions that are important for facilitating various aspects of neural programming in early development (80, 81).”
BackgroundInfluentialSznajder, Ł. J., Khan, M., Ciesiołka, A., Tadross, M., Nutter, C. A., Taylor, K., Pearson, C. E., Lewis, M. H., Hines, R. M., Swanson, M. S., et al. (2025) · Nature Neuroscience · doi:10.1038/s41593-025-01943-0 · Cited by 19
Diverse regulation of 3′ splice site usage
Sohail, M., & Xie, J. (2015) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-015-2037-5 · Cited by 18
“A more recent example of PTB-mediated repression of U2AF65 binding is its inhibition of neuron-enriched exons in non-neuronal cells [34].”
BackgroundFAIM-L regulation of XIAP degradation modulates Synaptic Long-Term Depression and Axon Degeneration
Martínez‐Mármol, R., Barneda‐Zahonero, B., Soto, D., Andrés, R. M., Coccia, E., Gasull, X., Planells‐Ferrer, L., Moubarak, R. S., Soriano, E., & Comella, J. X. (2016) · Scientific Reports · doi:10.1038/srep35775 · Cited by 16
Jeong, J., Yoo, H. J., An, J., & Jeong-Yu, S. (2025) · Molecules and Cells · doi:10.1016/j.mocell.2025.100237 · Cited by 15
“As a neuron-specific RBP, SRRM4 forms a uniquely organized RBP complex interacting with U2 snRNP subunits, binds to the 3’ splice site of neural exons, activating spliceosome assembly and counteracting PTBP-mediated repression (Raj et al., 2014).”
Regulation of Tissue-Specific Alternative Splicing: C. elegans as a Model System
Gracida, X., Norris, A. D., & Calarco, J. A. (2016) · Advances in experimental medicine and biology · doi:10.1007/978-3-319-29073-7_10 · Cited by 15
Nishtala, S., Neelamraju, Y., & Janga, S. C. (2016) · Scientific Reports · doi:10.1038/srep25711 · Cited by 14
Computational Analysis of Alternative Splicing Using VAST-TOOLS and the VastDB Framework
Gohr, A., Mantica, F., Hermoso, A., Tapial, J., Márquez, Y., & Irimia, M. (2022) · Methods in molecular biology · doi:10.1007/978-1-0716-2521-7_7 · Cited by 13
Self-citationThe spectrum of pre‐mRNA splicing in autism
Engal, E., Zhang, Z., Geminder, O., Jaffe‐Herman, S., Kay, G., Ben‐Hur, A., & Salton, M. (2024) · Wiley Interdisciplinary Reviews - RNA · doi:10.1002/wrna.1838 · Cited by 14
“The human brain has a specific configuration of splicing factor expression, creating distinct splicing patterns (Raj et al., 2014; van de Leemput et al., 2014) (Figure 2).”
BackgroundPost-transcriptional regulation of the transcriptional apparatus in neuronal development
Nazim, M. (2024) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2024.1483901 · Cited by 12
Gohr, A., Iñiguez, L., Torres-Méndez, A., Bonnal, S., & Irimia, M. (2023) · Nucleic Acids Research · doi:10.1093/nar/gkad244 · Cited by 12
“Third, a major feature previously associated with SRRM4-dependent microexons, namely weaker 3′ ss contexts in the upstream intron (27,35,36), was significantly more prominent for dofi microexons (Figure 7I; P = 0.”
Self-citationLeveraging transcript quantification for fast computation of alternative splicing profilesPreprint
Alamancos, G. P., Pagès, A., Trincado, J. L., Bellora, N., & Eyras, E. (2014) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/008763 · Cited by 12
Self-citationYang, Y. A., Lee, G. C., Nakagaki-Silva, E. E., Huang, Y., Peacey, M., Partridge, R., Gooding, C., & Smith, C. W. J. (2023) · Nucleic Acids Research · doi:10.1093/nar/gkad652 · Cited by 11
“Ne v ertheless, some splicing regulators show mor e r estricted expr ession and may act as master regulators of splicing programmes ( 13 , 16 ).”
BackgroundEvolution of the Human Brain Can Help Determine Pathophysiology of Neurodevelopmental Disorders
Irie, K., Doi, M., Usui, N., & Shimada, S. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.871979 · Cited by 11
CCAR1 promotes DNA repair via alternative splicing
Karasu, M. E., Jahnke, L., Joseph, B. J., Amerzhanova, Y., Mironov, A., Shu, X., Schröder, M., Gvozdenovic, A., Sala, I., Zavolan, M., et al. (2024) · Molecular Cell · doi:10.1016/j.molcel.2024.06.011 · Cited by 10
From Tiny Exons to Big Insights: The Expanding Field of Microexons
Mackensen, T., & Irimia, M. (2025) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-121323-103648 · Cited by 10
Self-citationPoliński, P., Miret-Cuesta, M., Zamora‐Moratalla, A., Mantica, F., Cantero-Recasens, G., Viana, C., Sabariego-Navarro, M., Normanno, D., Iñiguez, L., Morenilla‐Palao, C., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-59430-w · Cited by 21
“Additionally, in line with previous studies 32,33 , we found that the inclusion of the microexon was highly dependent on the action of the neuronal-speci fi c Ser/Arg Repetitive Matrix3 and 4 genes( SRRM3/4 ) in humans, mice and zebra fi sh (Fig.”
Self-citationXie, D., Wang, Z., Sun, B., Qu, L.-W., Zeng, M., Feng, L., Guo, M., Wang, G., Hao, J., & Zhou, G. (2023) · Frontiers of Medicine · doi:10.1007/s11684-023-1009-7 · Cited by 9
Rogalska, M. E., Vafiadaki, E., Erpapazoglou, Z., Haghighi, K., Green, L., Mantzoros, C. S., Hajjar, R. J., Tranter, M., Karakikes, I., Kranias, E. G., et al. (2022) · Metabolism · doi:10.1016/j.metabol.2022.155344 · Cited by 9
Distinct and Modular Organization of Protein Interacting Sites in Long Non-coding RNAs
Jalali, S., Gandhi, S., & Scaria, V. (2018) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2018.00027 · Cited by 9
“…Ligase X Baltz et al., 2012 56 SFRS1 Splicing factor arginine/serine-rich 1 X X Sanford et al., 2009 57 SRRM4 Serine/Arginine Repetitive Matrix 4 X Raj et al., 2014 58 TAF15 TATA-Box Binding Protein Associated Factor 15 X X X Hoell et al., 2011; Ibrahim et al., 2013 59 TARDBP/TDP-43 Transactive…”
BackgroundAlternative splicing in autism spectrum disorder: Recent insights from mechanisms to therapy
Zheng, M., Bao, N., Wang, Z., Song, C., & Jin, Y. (2025) · Asian Journal of Psychiatry · doi:10.1016/j.ajp.2025.104501 · Cited by 8
Unique transcriptomes of sensory and non-sensory neurons: insights from Splicing Regulatory States
Ciampi, L., Serrano, L. G., & Irimia, M. (2024) · Molecular Systems Biology · doi:10.1038/s44320-024-00020-1 · Cited by 10
“On the other hand, PTBP1 was found to antagonize the function of SRRM4 for a large fraction of microexons (Raj et al, 2014), and the core SF U2AF1 also has a conserved and somewhat unexpected role in repressing neural microexon inclusion (Torres-Méndez et al, 2022).”
BackgroundSelf-citationPorter, R. S., An, S., Gavilán, M. C., Nagai, M., Murata-Nakamura, Y., Zhou, B. O., Bonefas, K. M., Dionne, O., Manuel, J. M., St-Germain, J., et al. (2025) · Cell Reports · doi:10.1016/j.celrep.2024.115213 · Cited by 9
“25 The UGC sequence at the 3 ′ -splice site is an nSR100 binding motif, 12,64 and we observed that the region upstream of PHF21A-n exon has several UGCs.”
Coccia, E., Calleja‐Yagüe, I., Planells‐Ferrer, L., Sanuy, B., Sanz, B., López‐Soriano, J., Moubarak, R. S., Munell, F., Barneda‐Zahonero, B., Comella, J. X., et al. (2017) · PLoS ONE · doi:10.1371/journal.pone.0185327 · Cited by 9
Posttranscriptional and translational control of neurogenesis
Alsina, F. C., & Silver, D. L. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-814405-3.00028-x · Cited by 6
Poliński, P., Miret-Cuesta, M., Zamora‐Moratalla, A., Mantica, F., Cantero-Recasens, G., Normanno, D., Iñiguez, L., Morenilla‐Palao, C., Ordoño, P., Bonnal, S., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.01.12.523772 · Cited by 7
Self-citationThe splicing factor CCAR1 regulates the Fanconi anemia/BRCA pathway
Harada, N., Asada, S., Jiang, L., Nguyen, H. Q., Moreau, L. A., Marina, R. J., Adelman, K., Iyer, D., & D’Andrea, A. D. (2024) · Molecular Cell · doi:10.1016/j.molcel.2024.06.031 · Cited by 6
“24 Based on these findings, we hypothesized that CCAR1 loss caused a splicing error in FANCA transcript, and indeed, we found a poison exon with a stop codon between exon14 and exon15.”
Background
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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