Role of the cytoplasmic isoform of RBFOX1/A2BP1 in establishing the architecture of the developing cerebral cortex
Open accessAbstract
BACKGROUND: RBFOX1 (also known as FOX1 or A2BP1) regulates alternative splicing of a variety of transcripts crucial for neuronal functions. Physiological significance of RBFOX1 during brain development is seemingly essential since abnormalities in the gene cause autism spectrum disorder (ASD) and other neurodevelopmental and neuropsychiatric disorders such as intellectual disability, epilepsy, attention deficit hyperactivity disorder, and schizophrenia. RBFOX1 was also shown to serve as a "hub" in ASD gene transcriptome network. However, the pathophysiological significance of RBFOX1 gene abnormalities remains to be clarified. METHODS: To elucidate the pathophysiological relevance of Rbfox1, we performed a battery of in vivo and in vitro analyses of the brain-specific cytoplasmic isoform, Rbfox1-iso2, during mouse corticogenesis. In vivo analyses were based on in utero electroporation, and the role of Rbfox1-iso2 in cortical neuron migration, neurogenesis, and morphology was investigated by morphological methods including confocal laser microscope-assisted time-lapse imaging. In vitro analyses were carried out to examine the morphology of primary cultured mouse hippocampal neurons. RESULTS: Silencing of Rbfox1-iso2 in utero caused defects in the radial migration and terminal translocation of cortical neurons during corticogenesis. Time-lapse imaging revealed that radial migration was apparently impaired by dysregulated nucleokinesis. Rbfox1-iso2 also regulated neuronal network formation in vivo since axon extension to the opposite hemisphere and dendritic arborization were hampered by the knockdown. In in vitro analyses, spine density and mature spine number were reduced in Rbfox1-iso2-deficient hippocampal neurons. CONCLUSIONS: Impaired Rbfox1-iso2 function was found to cause abnormal corticogenesis during brain development. The abnormal process may underlie the basic pathophysiology of ASD and other neurodevelopmental disorders and may contribute to the emergence of the clinical symptoms of the patients with RBFOX1 gene abnormalities.
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Knockdown and silencing of RBFOX1 during mouse corticogenesis impairs neuronal migration and synapse formation.
“Knockdown and silencing of RBFOX1 during mouse corticogenesis impairs neuronal migration and synapse formation (Hamada et al., 2015; Hamada et al., 2016)”
From Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders (2019) · cites this paper as Hamada et al., 2015
RBFOX1 encodes a splicing regulator mainly expressed in neurons and known to target genes important for neuronal development, including NMDA receptor 1 and voltage-gated calcium channels.
“RBFOX1 (also called A2BP1 ) encodes a splicing regulator mainly expressed in neurons and known to target several genes important to neuronal development, including NMDA receptor 1 and voltage-gated calcium channels (Gandal et al., 2018; Gehman et al., 2011; Hamada et al., 2015).”
From Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders (2019) · cites this paper as Hamada et al., 2015
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Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders
Lee, P. H., Anttila, V., Won, H., Feng, Y.-C. A., Rosenthal, J., Zhu, Z., Tucker-Drob, E. M., Nivard, M. G., Grotzinger, A. D., Posthuma, D., et al. (2019) · Cell · doi:10.1016/j.cell.2019.11.020 · Cited by 1,381 · see citing works
“Knockdown and silencing of RBFOX1 during mouse corticogenesis impairs neuronal migration and synapse formation (Hamada et al., 2015; Hamada et al., 2016), implying its pivotal role in early cortical maturation.”
Background
- Authors
- Hamada, N., Ito, H., Iwamoto, I., Morishita, R., Tabata, H., & Nagata, K.-I.
- Affiliations
- Aichi Human Service Center (JP)
- Corresponding author
- Nagata, Koh-ichi
- Venue
- Molecular Autism
- Published
- 2015-10-20
- Volume
- 6
- Issue
- 1
- Pages
- 56-56
- ISSN
- 2040-2392 (ISSN-L)
- PMC
- PMC4617638
- OpenAlex
- W1945730826
- Cited by
- 59
- References
- 10
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 6 · 2023: 4 · 2022: 5 · 2021: 6 · 2020: 4 · 2019: 7 · 2018: 8 · 2017: 8 · 2016: 8
- FWCI
- 3.24
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Molecular Autism (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Ministry of Education, Science, Technology, Sports and Culture of Japan (24390271, 25122722, 25670488)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Fetal and Pediatric Neurological Disorders
- Keywords
- RBFOX1, A2BP1, cortical development, alternative splicing, autism spectrum disorder, neuronal migration, radial migration, neuronal network formation, dendritic branching, axon growth, hippocampal neurons, dendritic spine density, neurodevelopmental disorders
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