Abstract
BackgroundRBFOX1 (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.MethodsTo 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.ResultsSilencing 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.ConclusionsImpaired 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13229-015-0049-5) contains supplementary material, which is available to authorized users.
Highlights
RBFOX1 regulates alternative splicing of a variety of transcripts crucial for neuronal functions
PCAG-EGFP was electroporated in utero with pSuperH1.shLuc control or pSuper-mRbfox1-RNAi vectors into ventricular zone (VZ) progenitor cells of mice brains at E14.5, and localization of the transfected cells and their progeny was visualized at postnatal day (P) 3
While control neurons were positioned normally at the superficial layer of cortical plate (CP), a considerable portion of cells transfected with pSupermRbfox1-iso2 or pSuper-mRbfox1-iso1/2 remained in the lower zone of CP and intermediate zone (IZ) (Fig. 1b, c)
Summary
RBFOX1 ( 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. Fluorescence in situ hybridization (FISH), array comparative genomic hybridization (aCGH), and genomewide linkage studies (GWAS) have been demonstrated that RBFOX1 is associated with autism spectrum disorder (ASD) and other neuropsychiatric disorders including intellectual disabilities (IDs), epilepsy, attention deficit hyperactivity disorder (ADHD), and schizophrenia [6,7,8,9,10,11,12,13,14,15]. Abnormal reduction of RBFOX1 expression in a subset of ASD patient brains was correlated with altered splicing of its predicted targets including two ASD-related genes (GRIN1 and MEF2C), the pathophysiological relevance of the splicing variation remains to be elucidated [17]. Massive splicing changes were detected in 48 genes in a group of ASD patient brains where downregulation of RBFOX1 was estimated [18]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
