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Identification of Rbfox1 binding in the cytoplasm of neurons by iCLIP

ABSTRACT: Human genetic studies have identified the neuronal RNA binding protein, Rbfox1, as a candidate gene for autism spectrum disorders. While Rbfox1 functions as a splicing regulator in the nucleus, it is also alternatively spliced to produce cytoplasmic isoforms. To investigate cytoplasmic Rbfox1, we knocked down Rbfox proteins in mouse neurons and rescued with cytoplasmic or nuclear Rbfox1. Transcriptome profiling showed that nuclear Rbfox1 rescued splicing changes induced by knockdown, whereas cytoplasmic Rbfox1 rescued changes in mRNA levels. iCLIP-seq of subcellular fractions revealed that in nascent RNA Rbfox1 bound predominantly to introns, while cytoplasmic Rbox1 bound to 3' UTRs. Cytoplasmic Rbfox1 binding increased target mRNA stability and translation, and overlapped significantly with miRNA binding sites. Cytoplasmic Rbfox1 target mRNAs were enriched in genes involved in cortical development and autism. Our results uncover a new Rbfox1 regulatory network and highlight the importance of cytoplasmic RNA metabolism to cortical development and disease. In this data set, we included the data from iCLIP-seq experiments.

ORGANISM(S): Mus musculus

PROVIDER: GSE71790 | GEO | 2015/12/10

SECONDARY ACCESSION(S): PRJNA292090

REPOSITORIES: GEO

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Identification of Rbfox1 binding in the cytoplasm of neurons by iCLIP

Project description:Human genetic studies have identified the neuronal RNA binding protein, Rbfox1, as a candidate gene for autism spectrum disorders. While Rbfox1 functions as a splicing regulator in the nucleus, it is also alternatively spliced to produce cytoplasmic isoforms. To investigate cytoplasmic Rbfox1, we knocked down Rbfox proteins in mouse neurons and rescued with cytoplasmic or nuclear Rbfox1. Transcriptome profiling showed that nuclear Rbfox1 rescued splicing changes induced by knockdown, whereas cytoplasmic Rbfox1 rescued changes in mRNA levels. iCLIP-seq of subcellular fractions revealed that in nascent RNA Rbfox1 bound predominantly to introns, while cytoplasmic Rbox1 bound to 3' UTRs. Cytoplasmic Rbfox1 binding increased target mRNA stability and translation, and overlapped significantly with miRNA binding sites. Cytoplasmic Rbfox1 target mRNAs were enriched in genes involved in cortical development and autism. Our results uncover a new Rbfox1 regulatory network and highlight the importance of cytoplasmic RNA metabolism to cortical development and disease. In this data set, we included the data from iCLIP-seq experiments. We performed iCLIP procedures to identify Rbfox1 binding in the cytoplasm. Cultured mouse forebrain neurons were irradiated with UV and a cytoplasmic fraction was purified for immunoprecipitation. An anti-Rbfox1 antibody was used to immunoprecipitate Rbfox1 target RNAs and an anti-Flag antibody was used as control. Two samples were analyzed.

2015-12-10 | E-GEOD-71790 | biostudies-arrayexpress

Gene expression profiling of neurons with Rbfox1 and Rbfox3 knockdown and rescue with cytoplasmic or nuclear Rbfox1 isoform [RNA-seq]

Project description:Human genetic studies have identified the neuronal RNA binding protein, Rbfox1, as a candidate gene for autism spectrum disorders. While Rbfox1 functions as a splicing regulator in the nucleus, it is also alternatively spliced to produce cytoplasmic isoforms. To investigate cytoplasmic Rbfox1, we knocked down Rbfox proteins in mouse neurons and rescued with cytoplasmic or nuclear Rbfox1. Transcriptome profiling showed that nuclear Rbfox1 rescued splicing changes induced by knockdown, whereas cytoplasmic Rbfox1 rescued changes in mRNA levels. iCLIP-seq of subcellular fractions revealed that in nascent RNA Rbfox1 bound predominantly to introns, while cytoplasmic Rbox1 bound to 3' UTRs. Cytoplasmic Rbfox1 binding increased target mRNA stability and translation, and overlapped significantly with miRNA binding sites. Cytoplasmic Rbfox1 target mRNAs were enriched in genes involved in cortical development and autism. Our results uncover a new Rbfox1 regulatory network and highlight the importance of cytoplasmic RNA metabolism to cortical development and disease. In this data set, we included the data from RNA-seq experiments. We performed RNA-seq to profile gene expression and splicing changes. The expression levels of Rbfox1 and Rbfox3 in cultured mouse hippocampal neurons were reduced by siRNAs. The reduction of Rbfox1 and 3 was rescued by expression of cytoplasmic or nuclear Rbfox1 splice isoform. The gene expression and splicing profiles were compared between different treatments. Eight samples were analyzed.

2015-12-10 | E-GEOD-71916 | biostudies-arrayexpress

Gene expression profiling of neurons with Rbfox1 and Rbfox3 knockdown

Project description:Human genetic studies have identified the neuronal RNA binding protein, Rbfox1, as a candidate gene for autism spectrum disorders. While Rbfox1 functions as a splicing regulator in the nucleus, it is also alternatively spliced to produce cytoplasmic isoforms. To investigate cytoplasmic Rbfox1, we knocked down Rbfox proteins in mouse neurons and rescued with cytoplasmic or nuclear Rbfox1. Transcriptome profiling showed that nuclear Rbfox1 rescued splicing changes induced by knockdown, whereas cytoplasmic Rbfox1 rescued changes in mRNA levels. iCLIP-seq of subcellular fractions revealed that in nascent RNA Rbfox1 bound predominantly to introns, while cytoplasmic Rbox1 bound to 3' UTRs. Cytoplasmic Rbfox1 binding increased target mRNA stability and translation, and overlapped significantly with miRNA binding sites. Cytoplasmic Rbfox1 target mRNAs were enriched in genes involved in cortical development and autism. Our results uncover a new Rbfox1 regulatory network and highlight the importance of cytoplasmic RNA metabolism to cortical development and disease. In this data set, we included the data from microarray experiments. We performed microarray analysis to profile gene expression and splicing changes in mouse hippocampal cultures (14 DIV) with Rbfox1 and Rbfox3 double knockdown by siRNAs. Before the treatment of siRNAs, the hippocampal cultures were treated with AraC to eliminate glial cells and co-cultured with cortical cultures to support the growth of neurons. Six samples were analyzed.

2015-12-10 | E-GEOD-71974 | biostudies-arrayexpress

Gene expression profiling of neurons with Rbfox1 and Rbfox3 knockdown and rescue with cytoplasmic or nuclear Rbfox1 isoform [RNA-seq]

2015-12-10 | GSE71916 | GEO

Gene expression profiling of neurons with Rbfox1 and Rbfox3 knockdown

2015-12-10 | GSE71974 | GEO

RbFox1-Nestin hippocampus

Project description:Dysregulation of the brain-enriched RNA binding protein Rbfox1 has been linked to neurologic diseases such as epilepsy and autism spectrum disorders. However, it remains unexplored how distinct neuronal populations might contribute to neurologic dysfunction resulting from Rbfox1 loss. To examine these issues we profiled gene expression specifically in the hippocampus of wildtype and Rbfox1-/- mice. We identified transcripts whose expression was strongly Rbfox1-dependent and exhibited significant Rbfox1 binding in their 3’UTRs. One prominent target, Vamp1, was found to be specifically expressed in GABAergic interneurons. Both Vamp1 knockdown and Rbfox1 loss led to decreased synaptic transmission, and altered E/I balance in the Rbfox1-/- hippocampus, indicating that Vamp1 loss is a major component of the Rbfox1-/- physiological phenotype. The cytoplasmic isoform of Rbfox1 was sufficient to rescue Vamp1 expression in Rbfox1-/- neurons. We show that Rbfox1 binding in the Vamp1 3’UTR promotes its expression in part by antagonizing the brain-enriched microRNA-9. These results demonstrate that inhibitory neurons maintain specialized synaptic vesicle release machinery containing Vamp1 that is critically regulated by Rbfox1.

2018-04-04 | GSE96722 | GEO

Rbfox1 mediates cell-type specific splicing in cortical interneurons

Project description:Cortical interneurons display a remarkable diversity in their morphology, physiological properties and connectivity. Elucidating the molecular determinants underlying this heterogeneity is essential for understanding interneuron development and function. We discovered that alternative splicing differentially regulates the integration of somatostatin- and parvalbumin-expressing interneurons into nascent cortical circuits through the cell-type specific tailoring of mRNAs. Specifically, we identified a role for the activity-dependent splicing regulator Rbfox1 in the development of cortical interneuron subtype specific efferent connectivity. Our work demonstrates that Rbfox1 mediates largely non-overlapping alternative splicing programs within two distinct but related classes of interneurons.

2018-10-12 | GSE119998 | GEO

Rbfox1 up-regulation impairs BDNF-dependent hippocampal LTP by dysregulating TrkB isoform expression levels.

Project description:Brain Derived Neurotrophic Factor (BDNF) is a potent modulator of brain synaptic plasticity. Signaling defects caused by dysregulation of its NTrk2 (TrkB) kinase (TrkB.FL) and truncated receptors (TrkB.T1) have been linked to the pathophysiology of several neurological and neurodegenerative disorders. We found that upregulation of Rbfox1, an RNA binding protein associated with intellectual disability, epilepsy and autism, increases selectively hippocampal TrkB.T1 isoform expression. Physiologically, increased Rbfox1 impairs BDNF-dependent LTP which can be rescued by genetically restoring TrkB.T1 levels. RNA-seq analysis of hippocampi with upregulation of Rbfox1 in conjunction with the specific increase of TrkB.T1 isoform expression also shows that the genes affected by Rbfox1 gain of function are surprisingly different from those influenced by Rbfox1 deletion. These findings not only identify TrkB as a major target of Rbfox1 pathophysiology but also suggest that gain or loss of function of Rbfox1 regulate different genetic landscapes.

2019-08-24 | GSE136253 | GEO

DOWNREGULATION OF SPLICING REGULATOR RBFOX1 COMPROMISES VISUAL DEPTH PERCEPTION

Project description:Rbfox1 is a splicing regulator that has been associated with various neurological conditions such as autism spectrum disorder, mental retardation, epilepsy, attention-deficit/hyperactivity disorder, and schizophrenia. We show that in adult rodent retinas, Rbfox1 is expressed in all types of retinal ganglion cells (RGCs) as well as in certain subsets of amacrine cells (ACs) within the inner nuclear and ganglion cell layers. In developing retinas, Rbfox1 can be detected as early as E12. At that age, Rbfox1 is localized in the cytoplasm of differentiated RGCs. Between P0 and P5, strong expression of Rbfox1 in the inner plexiform layer was observed. This coincided with switching of Rbfox1 localization in RGC somas from cytoplasmic to a predominantly nuclear. Dynamic changes in Rbfox1 expression during first 10 postnatal days are correlated with the stage II spontaneous retinal waves of excitation, which in mice begins around the time of birth and continues for as long as two weeks. By P10, dendritic staining of Rbfox1 was dramatically reduced and remained so in the fully developed retina. In Rbfox1 knockout (KO) animals no detectable changes in retinal gross morphology were observed two months after Rbfox1 downregulation. However, the visual cliff test revealed marked abnormalities of depth perception of these animals. Retinal transcriptome analysis of Rbfox1 KO mice identified a number of genes that are involved in establishing neural circuits and synaptic transmission, including Vamp1, Vamp2, Snap25, Trak2, and Slc1A7, suggesting a role of Rbfox1 in the regulation of genes that facilitate AC and RGC synaptic communication.

2018-07-19 | GSE105084 | GEO

RBFOX1 Splicing and Transcriptional Regulation in Neurons

Project description: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 large set of alternative splicing events implicated in neurogenesis and cell maintenance. Subsequent alterations in gene expression define an additional transcriptional network regulated by RBFOX1 involved in neurodevelopmental pathways remarkably parallel to those affected by splicing. RNA sequencing at a 75bp single-end read scale was performed using polyA-enriched RNA from 5 biological replicates of primary human neural progenitor cell lines generated by lentiviral-mediated knockdown of GFP (control) or RBFOX1 and differentiated for 4 weeks.

2012-06-28 | E-GEOD-36710 | biostudies-arrayexpress

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