Cartography of neurexin alternative splicing mapped by single-molecule long-read mRNA sequencing.
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| Title: | Cartography of neurexin alternative splicing mapped by single-molecule long-read mRNA sequencing. |
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| Authors: | Treutlein, Barbara1,2, Ozgun Gokce3, Quake, Stephen R.1,2,4 quake@stanford.edu, Südhof, Thomas C.3,4 tcs1@stanford.edu |
| Source: | Proceedings of the National Academy of Sciences of the United States of America. 4/1/2014, Vol. 111 Issue 13, pE1291-E1299. 9p. |
| Subjects: | Neurexins, Cartography, Neural transmission, Schizophrenia, Autism |
| Abstract: | Neurexins are evolutionarily conserved presynaptic cell-adhesion molecules that are essential for normal synapse formation and synaptic transmission. Indirect evidence has indicated that extensive alternative splicing of neurexin mRNAs may produce hundreds if not thousands of neurexin isoforms, but no direct evidence for such diversity has been available. Here we use unbiased long-read sequencing of full-length neurexin (Nrxn)1α, Nrxn1β, Nrxn2β, Nrxn3α, and Nrxn3β mRNAs to systematically assess how many sites of alternative splicing are used in neurexins with a significant frequency, and whether alternative splicing events at these sites are independent of each other. In sequencing more than 25,000 full-length mRNAs, we identified a novel, abundantly used alternatively spliced exon of Nrxn1α and Nrxn3α (referred to as alternatively spliced sequence 6) that encodes a 9-residue insertion in the flexible hinge region between the fifth LNS (laminin-α, neurexin, sex hormone-binding globulin) domain and the third EGF-like sequence. In addition, we observed several larger-scale events of alternative splicing that deleted multiple domains and were much less frequent than the canonical six sites of alternative splicing in neurexins. All of the six canonical events of alternative splicing appear to be independent of each other, suggesting that neurexins may exhibit an even larger isoform diversity than previously envisioned and comprise thousands of variants. Our data are consistent with the notion that α-neurexins represent extracellular protein-interaction scaffolds in which different LNS and EGF domains mediate distinct interactions that affect diverse functions and are independently regulated by independent events of alternative splicing. [ABSTRACT FROM AUTHOR] |
| Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) | |
| Database: | Engineering Source |
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| Header | DbId: egs DbLabel: Engineering Source An: 95394845 AccessLevel: 6 PubType: Academic Journal PubTypeId: academicJournal PreciseRelevancyScore: 0 |
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| Items | – Name: Title Label: Title Group: Ti Data: Cartography of neurexin alternative splicing mapped by single-molecule long-read mRNA sequencing. – Name: Author Label: Authors Group: Au Data: <searchLink fieldCode="AR" term="%22Treutlein%2C+Barbara%22">Treutlein, Barbara</searchLink><relatesTo>1,2</relatesTo><br /><searchLink fieldCode="AR" term="%22Ozgun+Gokce%22">Ozgun Gokce</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Quake%2C+Stephen+R%2E%22">Quake, Stephen R.</searchLink><relatesTo>1,2,4</relatesTo><i> quake@stanford.edu</i><br /><searchLink fieldCode="AR" term="%22Südhof%2C+Thomas+C%2E%22">Südhof, Thomas C.</searchLink><relatesTo>3,4</relatesTo><i> tcs1@stanford.edu</i> – Name: TitleSource Label: Source Group: Src Data: <searchLink fieldCode="JN" term="%22Proceedings+of+the+National+Academy+of+Sciences+of+the+United+States+of+America%22">Proceedings of the National Academy of Sciences of the United States of America</searchLink>. 4/1/2014, Vol. 111 Issue 13, pE1291-E1299. 9p. – Name: Subject Label: Subjects Group: Su Data: <searchLink fieldCode="DE" term="%22Neurexins%22">Neurexins</searchLink><br /><searchLink fieldCode="DE" term="%22Cartography%22">Cartography</searchLink><br /><searchLink fieldCode="DE" term="%22Neural+transmission%22">Neural transmission</searchLink><br /><searchLink fieldCode="DE" term="%22Schizophrenia%22">Schizophrenia</searchLink><br /><searchLink fieldCode="DE" term="%22Autism%22">Autism</searchLink> – Name: Abstract Label: Abstract Group: Ab Data: Neurexins are evolutionarily conserved presynaptic cell-adhesion molecules that are essential for normal synapse formation and synaptic transmission. Indirect evidence has indicated that extensive alternative splicing of neurexin mRNAs may produce hundreds if not thousands of neurexin isoforms, but no direct evidence for such diversity has been available. Here we use unbiased long-read sequencing of full-length neurexin (Nrxn)1α, Nrxn1β, Nrxn2β, Nrxn3α, and Nrxn3β mRNAs to systematically assess how many sites of alternative splicing are used in neurexins with a significant frequency, and whether alternative splicing events at these sites are independent of each other. In sequencing more than 25,000 full-length mRNAs, we identified a novel, abundantly used alternatively spliced exon of Nrxn1α and Nrxn3α (referred to as alternatively spliced sequence 6) that encodes a 9-residue insertion in the flexible hinge region between the fifth LNS (laminin-α, neurexin, sex hormone-binding globulin) domain and the third EGF-like sequence. In addition, we observed several larger-scale events of alternative splicing that deleted multiple domains and were much less frequent than the canonical six sites of alternative splicing in neurexins. All of the six canonical events of alternative splicing appear to be independent of each other, suggesting that neurexins may exhibit an even larger isoform diversity than previously envisioned and comprise thousands of variants. Our data are consistent with the notion that α-neurexins represent extracellular protein-interaction scaffolds in which different LNS and EGF domains mediate distinct interactions that affect diverse functions and are independently regulated by independent events of alternative splicing. [ABSTRACT FROM AUTHOR] – Name: AbstractSuppliedCopyright Label: Group: Ab Data: <i>Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.) |
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| RecordInfo | BibRecord: BibEntity: Identifiers: – Type: doi Value: 10.1073/pnas.1403244111 Languages: – Code: eng Text: English PhysicalDescription: Pagination: PageCount: 9 StartPage: E1291 Subjects: – SubjectFull: Neurexins Type: general – SubjectFull: Cartography Type: general – SubjectFull: Neural transmission Type: general – SubjectFull: Schizophrenia Type: general – SubjectFull: Autism Type: general Titles: – TitleFull: Cartography of neurexin alternative splicing mapped by single-molecule long-read mRNA sequencing. Type: main BibRelationships: HasContributorRelationships: – PersonEntity: Name: NameFull: Treutlein, Barbara – PersonEntity: Name: NameFull: Ozgun Gokce – PersonEntity: Name: NameFull: Quake, Stephen R. – PersonEntity: Name: NameFull: Südhof, Thomas C. IsPartOfRelationships: – BibEntity: Dates: – D: 01 M: 04 Text: 4/1/2014 Type: published Y: 2014 Identifiers: – Type: issn-print Value: 00278424 Numbering: – Type: volume Value: 111 – Type: issue Value: 13 Titles: – TitleFull: Proceedings of the National Academy of Sciences of the United States of America Type: main |
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