Essential roles for the splicing regulator nSR100/SRRM4 during nervous system development
Open accessAbstract
Alternative splicing (AS) generates vast transcriptomic complexity in the vertebrate nervous system. However, the extent to which trans -acting splicing regulators and their target AS regulatory networks contribute to nervous system development is not well understood. To address these questions, we generated mice lacking the vertebrate- and neural-specific Ser/Arg repeat-related protein of 100 kDa (nSR100/SRRM4). Loss of nSR100 impairs development of the central and peripheral nervous systems in part by disrupting neurite outgrowth, cortical layering in the forebrain, and axon guidance in the corpus callosum. Accompanying these developmental defects are widespread changes in AS that primarily result in shifts to nonneural patterns for different classes of splicing events. The main component of the altered AS program comprises 3- to 27-nucleotide (nt) neural microexons, an emerging class of highly conserved AS events associated with the regulation of protein interaction networks in developing neurons and neurological disorders. Remarkably, inclusion of a 6-nt, nSR100-activated microexon in Unc13b transcripts is sufficient to rescue a neuritogenesis defect in nSR100 mutant primary neurons. These results thus reveal critical in vivo neurodevelopmental functions of nSR100 and further link these functions to a conserved program of neuronal microexon splicing.
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Germline deletion of Srrm4 results in fewer Pax6+ cells in the ventricular zone and fewer postmitotic NeuN+ neurons.
“the germline deletion of Srrm4 results in fewer Pax6+ cells in the ventricular zone and fewer postmitotic NeuN+ neurons35”
From The neurogenetics of alternative splicing (2016) · cites this paper as [35]
Insufficient phrenic innervation to the diaphragm in Srrm4Δ7-8 mice appears to result from reduced secondary branching of motor neuron axons.
“This appears to result from insufficient phrenic innervation to the diaphragm35, as secondary branching of motor neuron axons in this region is reduced by twofold.”
From The neurogenetics of alternative splicing (2016) · cites this paper as [35]
Srrm4Δ7-8 mice show no gross morphological phenotype during embryonic development, but most die from respiratory failure within a few hours of birth.
“Srrm4Δ7–8 mice show no gross morphological phenotype during embryonic development, but most die from respiratory failure within a few hours of birth.”
From The neurogenetics of alternative splicing (2016) · cites this paper as [35]
Srrm4−/− mice have fewer late-born, upper-layer neurons and more early-born, lower-layer neurons.
“Srrm4−/− mice have fewer late-born, upper-layer neurons and more early-born, lower-layer neurons”
From The neurogenetics of alternative splicing (2016) · cites this paper as [35]
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Self-citationThe neurogenetics of alternative splicing
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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 · see citing works
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- Authors
- Quesnel-Vallières, M., Irimia, M., Cordes, S. P., & Blencowe, B. J.
- Affiliations
- Mount Sinai Hospital (CA)
- University of Toronto (CA)
- Corresponding author
- Cordes, Sabine P.
- Blencowe, Benjamin J.
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2015-04-01
- Volume
- 29
- Issue
- 7
- Pages
- 746-759
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC4387716
- OpenAlex
- W2054177024
- Cited by
- 155
- References
- 56
- Citations by year
- 2026: 10 · 2025: 20 · 2024: 16 · 2023: 8 · 2022: 16 · 2021: 14 · 2020: 12 · 2019: 13 · 2018: 13 · 2017: 13 · 2016: 13 · 2015: 6 · 2013: 1
- Type
- posted content
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Genes & Development (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research (MOP-67011, MOP-14609, MOP-111199)
- Human Frontiers Science Program Organization
- CIHR Banting and Best Scholarship
- Ontario Graduate Scholarship
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- alternative splicing, brain development, microexons, neurite outgrowth, cortical lamination, axon guidance, corpus callosum, neural development, mouse mutants
- MeSH terms
- Animals, Embryo, Mammalian, Exons, Mice, Inbred C57BL, Mice, Inbred ICR, Mutation, Nerve Tissue Proteins, Nervous System, RNA Splicing, Sequence Analysis, RNA, Mice, Neurogenesis
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