SAM68 Regulates Neuronal Activity-Dependent Alternative Splicing of Neurexin-1
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The assembly of synapses and neuronal circuits relies on an array of molecular recognition events and their modification by neuronal activity. Neurexins are a highly polymorphic family of synaptic receptors diversified by extensive alternative splicing. Neurexin variants exhibit distinct isoform-specific biochemical interactions and synapse assembly functions, but the mechanisms governing splice isoform choice are not understood. We demonstrate that Nrxn1 alternative splicing is temporally and spatially controlled in the mouse brain. Neuronal activity triggers a shift in Nrxn1 splice isoform choice via calcium/calmodulin-dependent kinase IV signaling. Activity-dependent alternative splicing of Nrxn1 requires the KH-domain RNA-binding protein SAM68 that associates with RNA response elements in the Nrxn1 pre-mRNA. Our findings uncover SAM68 as a key regulator of dynamic control of Nrxn1 molecular diversity and activity-dependent alternative splicing in the central nervous system.
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Neuronal activity controls alternative splicing of neurexin mRNA, which changes trans-synaptic signalling and presynaptic differentiation.
“Neuronal activity also regulates alternative splicing of neurexin mRNA and, thus, alters trans-synaptic signalling and presynaptic differentiation45.”
From Activity-dependent neuronal signalling and autism spectrum disorder (2013) · cites this paper as [45]
In cerebellar granule neurons, KCl depolarization and kainic acid treatment increase SAM68 phosphorylation at Ser20 via CamKIV activation, leading to increased repression of Nrxn1 exon 20.
“In cerebellar granule neurons, both KCl depolarization and kainic acid treatment increase SAM68 phosphorylation at Ser20 via CamKIV activation, leading to increased repression of Nrxn1 exon 20 and changes in trans-synaptic interactions94”
From The neurogenetics of alternative splicing (2016) · cites this paper as [94]
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- Authors
- Iijima, T., Wu, K., Witte, H., Hanno-Iijima, Y., Glatter, T., Richard, S., & Scheiffele, P.
- Affiliations
- University of Basel (CH)
- Columbia University (US)
- Lady Davis Institute for Medical Research (CA)
- Corresponding author
- Scheiffele, Peter
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2011-12
- Volume
- 147
- Issue
- 7
- Pages
- 1601-1614
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3246220
- OpenAlex
- W2064800718
- Cited by
- 279
- References
- 79
- Citations by year
- 2026: 11 · 2025: 19 · 2024: 12 · 2023: 17 · 2022: 15 · 2021: 18 · 2020: 27 · 2019: 12 · 2018: 16 · 2017: 14 · 2016: 34 · 2015: 20 · 2014: 25 · 2013: 29 · 2012: 9
- FWCI
- 8.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Canadian Institutes of Health Research
- National Institute of Neurological Disorders and Stroke (R21 NS53936, R21NS053936)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Keywords
- Sam68, NRXN1, alternative splicing, activity-dependent gene regulation, synaptic receptors, pre-mRNA splicing, central nervous system
- MeSH terms
- Animals, Base Sequence, Calcium-Binding Proteins, Cerebellum, Humans, Molecular Sequence Data, Neurons, RNA-Binding Proteins, Alternative Splicing, Mice, Knockout, Neural Cell Adhesion Molecules, Response Elements, Adaptor Proteins, Signal Transducing, Mice
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