Stepwise assembly of the Nova -regulated alternative splicing network in the vertebrate brain
Open accessAbstract
Novel organismal structures in metazoans are often undergirded by complex gene regulatory networks; as such, understanding the emergence of new structures through evolution requires reconstructing the series of evolutionary steps leading to these underlying networks. Here, we reconstruct the step-by-step assembly of the vertebrate splicing network regulated by Nova, a splicing factor that modulates alternative splicing in the vertebrate central nervous system by binding to clusters of YCAY motifs on pre-RNA transcripts. Transfection of human HEK293T cells with Nova orthologs indicated vertebrate-like splicing regulatory activity in bilaterian invertebrates, thus Nova acquired the ability to bind YCAY clusters and perform vertebrate-like splicing modulation at least before the last common ancestor of bilaterians. In situ hybridization studies in several species showed that Nova expression became restricted to CNS later on, during chordate evolution. Finally, comparative genomics studies revealed a diverse history for Nova-regulated exons, with target exons arising through both de novo exon creation and acquisition of YCAY motifs by preexisting exons throughout chordate and vertebrate history. In addition, we find that tissue-specific Nova expression patterns emerged independently in other lineages, suggesting independent assembly of tissue-specific regulatory networks.
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Alternative splicing is particularly prevalent in the central nervous system and plays a crucial role in generating synaptic protein complexity.
“Alternative splicing, a process where different combinations of exons are included in the final mRNA transcript, is particularly prevalent in the central nervous system and plays a crucial role in generating synaptic protein complexity [88].”
From Molecular Physiology of the Neuronal Synapse (2026) · cites this paper as [88]
Cites
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“Nova regulates specific exons by binding to clusters of tetranucleotide [CU]CA[CU] (YCAY) motifs in exons or near splice sites in pre-mRNAs; depending on the position of Nova-binding sites relative to splice sites, Nova can either enhance or inhibit the inclusion of a particular exon in transcripts (12, 13).”
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- Authors
- Irimia, M., Denuc, A., Burguera, D., Somorjai, I., Martín-Durán, J. M., Genikhovich, G., Jimenez-Delgado, S., Technau, U., Roy, S. W., Marfany, G., & Garcia-Fernàndez, J.
- Affiliations
- Universitat de Barcelona (ES)
- Departament de Genètica, Facultat de Biologia, Universitat de Barcelona, Barcelona E08028, Spain;
- University of Vienna (AT)
- Stanford University (US)
- Institut de Biomedicina de la Universitat de Barcelona (ES)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2011-03-09
- Volume
- 108
- Issue
- 13
- Pages
- 5319-5324
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3069165
- OpenAlex
- W2061481049
- Cited by
- 47
- References
- 0
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 2 · 2022: 6 · 2021: 8 · 2020: 2 · 2019: 2 · 2017: 3 · 2016: 3 · 2015: 4 · 2014: 1 · 2013: 2 · 2012: 4
- FWCI
- 1.43
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Generalitat de Catalunya
- Institució Catalana de Recerca i Estudis Avançats
- Ministerio de Ciencia e Innovación
- Norges Forskningsråd
- Universitat de Barcelona
- FP7 People: Marie-Curie Actions
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- nova, alternative splicing, vertebrate brain evolution, chordate evolution, tissue-specific gene regulation, central nervous system, exonic splicing enhancers
- MeSH terms
- Neuro-Oncological Ventral Antigen, Animals, Antigens, Neoplasm, Brain, Humans, Molecular Sequence Data, Nerve Tissue Proteins, Vertebrates, RNA-Binding Proteins, Alternative Splicing, Gene Expression Regulation, Developmental, Evolution, Molecular, Mice, Gene Regulatory Networks, HEK293 Cells
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