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RBFOX1 regulates both splicing and transcriptional networks in human neuronal development
Open accessAbstract
RNA splicing plays a critical role in the programming of neuronal differentiation and, consequently, normal human neurodevelopment, and its disruption may underlie neurodevelopmental and neuropsychiatric disorders. The RNA-binding protein, fox-1 homolog (RBFOX1; also termed A2BP1 or FOX1), is a neuron-specific splicing factor predicted to regulate neuronal splicing networks clinically implicated in neurodevelopmental disease, including autism spectrum disorder (ASD), but only a few targets have been experimentally identified. We used RNA sequencing to identify the RBFOX1 splicing network at a genome-wide level in primary human neural stem cells during differentiation. We observe that RBFOX1 regulates a wide range of alternative splicing events implicated in neuronal development and maturation, including transcription factors, other splicing factors and synaptic proteins. Downstream alterations in gene expression define an additional transcriptional network regulated by RBFOX1 involved in neurodevelopmental pathways remarkably parallel to those affected by splicing. Several of these differentially expressed genes are further implicated in ASD and related neurodevelopmental diseases. Weighted gene co-expression network analysis demonstrates a high degree of connectivity among these disease-related genes, highlighting RBFOX1 as a key factor coordinating the regulation of both neurodevelopmentally important alternative splicing events and clinically relevant neuronal transcriptional programs in the development of human neurons.
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“An important piece of information missing in previous efforts toward this aim [e.g., (Fogel et al., 2012; Gehman et al., 2012; Gehman et al., 2011; Ray et al., 2013; Zhang et al., 2008)] is a genome-wide, high-resolution map ofin vivo Rbfox interaction sites in the brain.”
From HITS-CLIP and integrative modeling define the Rbfox splicing-regulatory network linked to brain development and autism (2014) · cites this paper as Fogel et al., 2012
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“we examined published RNA-seq data following RBFOX1 knockdown by RNA interference (RNAi)36 and found that the predicted RBFOX1 stability targets were collectively reduced in abundance (P < 10−15”
From A compendium of RNA-binding motifs for decoding gene regulation (2013) · cites this paper as [36]
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Metadata
- Authors
- Fogel, B. L., Wexler, E., Wahnich, A., Friedrich, T., Vijayendran, C., Gao, F., Parikshak, N., Konopka, G., & Geschwind, D. H.
- Affiliations
- University of California, Los Angeles (US)
- Corresponding author
- Fogel, Brent L.
- Geschwind, Daniel H.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2012-06-23
- Volume
- 21
- Issue
- 19
- Pages
- 4171-4186
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- PMC
- PMC3441119
- OpenAlex
- W2127061112
- Cited by
- 216
- References
- 85
- Citations by year
- 2026: 19 · 2025: 13 · 2024: 13 · 2023: 12 · 2022: 12 · 2021: 12 · 2020: 13 · 2019: 12 · 2018: 14 · 2017: 8 · 2016: 17 · 2015: 31 · 2014: 18 · 2013: 18 · 2012: 4
- FWCI
- 9.12
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- other-oa
- Locations
- Human Molecular Genetics (publishedVersion, other-oa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- California Institute of Technology
- National Institutes of Health (5r01mh094714-04)
- National Institute of Mental Health (R01-MH094714, R00MH090238, K08MH086297, K08MH074362, R01MH081754, T32MH073526, R37MH060233, K08MH86297)
- National Institute of General Medical Sciences (T32GM008042)
- National Institute of Child Health and Human Development
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD004612)
- 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 › RNA regulation and disease
- Keywords
- RBFOX1, A2BP1, alternative splicing, neuronal development, human neural stem cells, transcriptional regulatory networks, autism spectrum disorder, neurodevelopmental disorders, synaptic proteins, transcription factors, splicing factors, gene co-expression network, neuronal differentiation
- MeSH terms
- RNA Splicing Factors, Brain, Humans, RNA-Binding Proteins, Alternative Splicing, Aborted Fetus, Gene Regulatory Networks, Neurogenesis, Neural Stem Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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