Cross-Regulation between an Alternative Splicing Activator and a Transcription Repressor Controls Neurogenesis
Open accessAbstract
Neurogenesis requires the concerted action of numerous genes that are regulated at multiple levels. However, how different layers of gene regulation are coordinated to promote neurogenesis is not well understood. We show that the neural-specific Ser/Arg repeat-related protein of 100 kDa (nSR100/SRRM4) negatively regulates REST (NRSF), a transcriptional repressor of genes required for neurogenesis. nSR100 directly promotes alternative splicing of REST transcripts to produce a REST isoform (REST4) with greatly reduced repressive activity, thereby activating expression of REST targets in neural cells. Conversely, REST directly represses nSR100 in nonneural cells to prevent the activation of neural-specific splicing events. Consistent with a critical role for nSR100 in the inhibition of REST activity, blocking nSR100 expression in the developing mouse brain impairs neurogenesis. Our results thus reveal a fundamental role for direct regulatory interactions between a splicing activator and transcription repressor in the control of the multilayered regulatory programs required for neurogenesis.
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REST inhibits Srrm4 expression in non-neuronal cells.
“Conversely, REST inhibits Srrm4 expression in non-neuronal cells31.”
From The neurogenetics of alternative splicing (2016) · cites this paper as [31]
Knockdown of Srrm4 in the developing mouse cortex inhibits neuronal differentiation and leads to accumulation of Pax6+ progenitor cells in the ventricular zone and depletion of differentiated cells from the cortical plate.
“Knockdown of Srrm4 in the developing mouse cortex inhibits neuronal differentiation and leads to the accumulation of Pax6+ progenitor cells in the ventricular zone and the depletion of differentiated cells from the cortical plate31.”
From The neurogenetics of alternative splicing (2016) · cites this paper as [31]
SRRM4 promotes splicing of the REST4 isoform, which has reduced transcriptional repression activity.
“SRRM4 promotes splicing of the REST4 isoform, which lacks four of the nine zinc fingers found in the full-length protein31 and has reduced transcriptional repression activity32–34.”
From The neurogenetics of alternative splicing (2016) · cites this paper as [31]
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- Authors
- Raj, B., O'Hanlon, D., Vessey, J. P., Pan, Q., Ray, D., Buckley, N. J., Miller, F. D., & Blencowe, B. J.
- Affiliations
- University of Toronto (CA)
- Hospital for Sick Children (CA)
- King's College London (GB)
- Corresponding author
- Blencowe, Benjamin J.
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2011-09
- Volume
- 43
- Issue
- 5
- Pages
- 843-850
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W1997254455
- Cited by
- 143
- References
- 33
- Citations by year
- 2026: 3 · 2025: 9 · 2024: 6 · 2023: 11 · 2022: 8 · 2021: 7 · 2020: 9 · 2019: 11 · 2018: 9 · 2017: 13 · 2016: 9 · 2015: 13 · 2014: 11 · 2013: 9 · 2012: 14
- FWCI
- 3.67
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 721 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (King's College London) (submittedVersion)
- Funders
- Genome Canada
- Ontario Genomics Institute
- Hospital for Sick Children
- Canadian Institutes of Health Research
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- 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
- Keywords
- neurogenesis, SRRM4, rest, alternative splicing, transcriptional repression, transcriptional repressor, cross-regulation, neural development, brain development
- MeSH terms
- RE1-Silencing Transcription Factor, Animals, Cells, Cultured, Mice, Inbred Strains, Nerve Tissue Proteins, Neurons, Repressor Proteins, RNA Splicing, Transcription Factors, Transcription, Genetic, Alternative Splicing, Protein Isoforms, Mice, Neurogenesis
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