Rbfox3-regulated alternative splicing of Numb promotes neuronal differentiation during development
Open accessAbstract
Alternative premRNA splicing is a major mechanism to generate diversity of gene products. However, the biological roles of alternative splicing during development remain elusive. Here, we focus on a neuron-specific RNA-binding protein, Rbfox3, recently identified as the antigen of the widely used anti-NeuN antibody. siRNA-mediated loss-of-function studies using the developing chicken spinal cord revealed that Rbfox3 is required to promote neuronal differentiation of postmitotic neurons. Numb premRNA encoding a signaling adaptor protein was found to be a target of Rbfox3 action, and Rbfox3 repressed the inclusion of an alternative exon via binding to the conserved UGCAUG element in the upstream intron. Depleting a specific Numb splice isoform reproduced similar neuronal differentiation defects. Forced expression of the relevant Numb splice isoform was sufficient to rescue, in an isoform-specific manner, postmitotic neurons from defects in differentiation caused by Rbfox3 depletion. Thus, Rbfox3-dependent Numb alternative splicing plays an important role in the progression of neuronal differentiation during vertebrate development.
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Together with neuro-developmental defects seen in cell cultures, animal models, and human patients with disrupted Rbfox proteins, this provides a compelling case that Rbfox proteins play critical roles in driving the global dynamic change of the developmental splicing-regulatory program.
“Combined with neuro-developmental defects observed in cell cultures (Kim et al., 2013), animal models (Gehman et al., 2012; Gehman et al., 2011; Kim et al., 2013), and human patients (Bhalla et al., 2004) where Rbfox proteins are disrupted, this presents a compelling case for Rbfox proteins playing critical roles in driving the global dynamic change of the developmentalsplicing-regulatory program.”
From HITS-CLIP and integrative modeling define the Rbfox splicing-regulatory network linked to brain development and autism (2014) · cites this paper as Kim et al., 2013
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RETRACTED: RBFOX3 Promotes Gastric Cancer Growth and Progression by Activating HTERT Signaling
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- Authors
- Kim, K. K., Nam, J., Mukouyama, Y.-S., & Kawamoto, S.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Kawamoto, Sachiyo
- Venue
- Journal of Cell Biology
- Publisher
- Rockefeller University Press
- Published
- 2013-02-18
- Volume
- 200
- Issue
- 4
- Pages
- 443-458
- ISSN
- 0021-9525 (ISSN-L)
- 1540-8140
- PMC
- PMC3575530
- OpenAlex
- W2142550690
- Cited by
- 120
- References
- 41
- Citations by year
- 2026: 3 · 2025: 11 · 2024: 5 · 2023: 21 · 2022: 8 · 2021: 7 · 2020: 6 · 2019: 5 · 2018: 10 · 2017: 10 · 2016: 12 · 2015: 11 · 2014: 9 · 2013: 2
- FWCI
- 5.07
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Cell Biology (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Heart, Lung, and Blood Institute
- NHLBI Division of Intramural Research
- 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 › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- NeuN, Numb, alternative splicing, neuronal differentiation, RNA-binding proteins, postmitotic neurons, introns, splice variants, vertebrate development
- MeSH terms
- Animals, Binding Sites, Cell Line, Chick Embryo, DNA-Binding Proteins, Membrane Proteins, Nerve Tissue Proteins, Neurons, Nuclear Proteins, RNA Precursors, RNA, Messenger, Alternative Splicing, Protein Isoforms, Regulatory Elements, Transcriptional, Mice, Neural Tube, Neurogenesis
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