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Nova proteins direct synaptic integration of somatostatin interneurons through activity- dependent alternative splicing

ABSTRACT: Somatostatin interneurons are the earliest born population of inhibitory cells. They are crucial to support normal brain development and function; however, the mechanisms underlying their integration into nascent cortical circuitry are not well understood. In this study, we begin by demonstrating that the maturation of somatostatin interneurons is activity dependent. We then investigated the relationship between activity, alternative splicing and synapse formation within this population. Specifically, we discovered that the Nova family of RNA-binding proteins are activity-dependent and are essential for the maturation of somatostatin interneurons, as well as their afferent and efferent connectivity. Moreover, in somatostatin interneurons, Nova2 preferentially mediates the alternative splicing of genes required for axonal formation and synaptic function. Hence, our work demonstrates that the Nova family of proteins are centrally involved in coupling developmental neuronal activity to cortical circuit formation.

ORGANISM(S): Mus musculus

PROVIDER: GSE143316 | GEO | 2023/06/20

REPOSITORIES: GEO

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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

Wild type vs. Nova2 KO mouse P10 cortex RNA

Project description:To assess the requirement of Nova2 for alternative processing of RNA in mouse brain. Protein-RNA interactions play critical roles in all aspects of gene expression. Here we develop a genome-wide means of mapping protein-RNA binding sites in vivo, by high throughput sequencing of RNA isolated by crosslinking immunoprecipitation (HITS-CLIP). HITS-CLIP analysis of the neuron-specific splicing factor Nova2 revealed extremely reproducible RNA binding maps in multiple mouse brains. These maps provide genome-wide in vivo biochemical footprints confirming the previous prediction that the position of Nova binding determines the outcome of alternative splicing; moreover, they are sufficiently powerful to predict Nova action de novo. HITS-CLIP revealed a large number of Nova-RNA interactions in 3â UTRs, leading to the discovery that Nova regulates alternative polyadenylation in the brain. HITS-CLIP, therefore, provides a robust, unbiased means to identify functional protein-RNA interactions in vivo. Keywords: Comparative analysis Refer to individual Series. This SuperSeries is composed of the following subset Series: GSE17374: Wild type vs. Nova2 KO mouse: Exon array data GSE17376: Wild type vs. Nova2 KO mouse: Exon junction array data

2010-06-20 | E-GEOD-12965 | biostudies-arrayexpress

Wild type vs. Nova2 KO mouse E14.5 cortex RNA

Project description:To assess the requirement of Nova2 for alternative processing of RNA in the developping brain. Neuronal migration leads to a highly organized laminar structure in the mammalian brain and its mis-regulation causes lissencephaly, behavioral and cognitive defects. Reelin signaling, mediated in part by a key adaptor, disabled-1 (Dab1), plays a critical but incompletely understood role in this process. We found that the neuron-specific RNA binding protein Nova2 regulates neuronal migration in late-generated cortical and Purkinje neurons. An unbiased HITS-CLIP and exon junction array search for Nova-dependent RNAs at E14.5 focused on components of the reelin pathway revealed only one candidate—an alternatively spliced isoform of Dab1 (Dab1.7bc). In utero electroporation demonstrated that Dab1.7bc was sufficient to induce neuronal migration defects in wild-type mice and exacerbate defects when Dab1 levels were reduced, while Dab1 overexpression mitigates defects in Nova2-null mice. Thus Nova2 regulates an RNA switch controlling the ability of Dab1 to mediate neuronal responsiveness to reelin signaling and neuronal migration, suggesting new links between splicing regulation, brain disease and development. Keywords: Comparative analysis RNA from the cortex of 3 wild type and 3 Nova2 KO E14.5 cortex. One array per biological replicate.

2010-07-07 | E-GEOD-22758 | biostudies-arrayexpress

Wild type vs. Nova2 KO mouse: Exon junction array data

Project description:To assess the requirement of Nova2 for alternative processing of RNA in mouse brain. Protein-RNA interactions play critical roles in all aspects of gene expression. Here we develop a genome-wide means of mapping protein-RNA binding sites in vivo, by high throughput sequencing of RNA isolated by crosslinking immunoprecipitation (HITS-CLIP). HITS-CLIP analysis of the neuron-specific splicing factor Nova2 revealed extremely reproducible RNA binding maps in multiple mouse brains. These maps provide genome-wide in vivo biochemical footprints confirming the previous prediction that the position of Nova binding determines the outcome of alternative splicing; moreover, they are sufficiently powerful to predict Nova action de novo. HITS-CLIP revealed a large number of Nova-RNA interactions in 3’ UTRs, leading to the discovery that Nova regulates alternative polyadenylation in the brain. HITS-CLIP, therefore, provides a robust, unbiased means to identify functional protein-RNA interactions in vivo.

2009-11-04 | GSE17376 | GEO

Wild type vs. Nova2 KO mouse: Exon array data

Project description:To assess the requirement of Nova2 for alternative processing of RNA in mouse brain. Protein-RNA interactions play critical roles in all aspects of gene expression. Here we develop a genome-wide means of mapping protein-RNA binding sites in vivo, by high throughput sequencing of RNA isolated by crosslinking immunoprecipitation (HITS-CLIP). HITS-CLIP analysis of the neuron-specific splicing factor Nova2 revealed extremely reproducible RNA binding maps in multiple mouse brains. These maps provide genome-wide in vivo biochemical footprints confirming the previous prediction that the position of Nova binding determines the outcome of alternative splicing; moreover, they are sufficiently powerful to predict Nova action de novo. HITS-CLIP revealed a large number of Nova-RNA interactions in 3’ UTRs, leading to the discovery that Nova regulates alternative polyadenylation in the brain. HITS-CLIP, therefore, provides a robust, unbiased means to identify functional protein-RNA interactions in vivo.

2009-11-04 | GSE17374 | GEO

Integrative modeling defines the Nova splicing-regulatory network and its combinatorial controls: Exon array data

Project description:The control of RNA alternative splicing is critical for generating biological diversity. Despite emerging genome-wide technologies to study RNA complexity, reliable and comprehensive RNA-regulatory networks have not been defined. Here we used Bayesian networks to probabilistically model diverse datasets and predict the target networks of specific regulators. We applied this strategy to identify ~700 alternative splicing events directly regulated by the neuron-specific factor Nova in the mouse brain, integrating RNA-binding data, splicing microarray data, Nova-binding motifs, and evolutionary signatures. The resulting integrative network revealed combinatorial regulation by Nova and the neuronal splicing factor Fox, interplay between phosphorylation and splicing, and potential links to neurologic disease. Thus we have developed a general approach to understanding mammalian RNA regulation at the systems level. RNA from the whole brain or spinal cord of 4 wild type and 4 Nova1/2 double KO (dKO) E18.5 CD1 mice. One array per biological replicate.

2010-08-04 | E-GEOD-22115 | biostudies-arrayexpress

Wild type vs. Nova2 KO mouse P10 cortex RNA

Project description:To assess the requirement of Nova2 for alternative processing of RNA in mouse brain. Protein-RNA interactions play critical roles in all aspects of gene expression. Here we develop a genome-wide means of mapping protein-RNA binding sites in vivo, by high throughput sequencing of RNA isolated by crosslinking immunoprecipitation (HITS-CLIP). HITS-CLIP analysis of the neuron-specific splicing factor Nova2 revealed extremely reproducible RNA binding maps in multiple mouse brains. These maps provide genome-wide in vivo biochemical footprints confirming the previous prediction that the position of Nova binding determines the outcome of alternative splicing; moreover, they are sufficiently powerful to predict Nova action de novo. HITS-CLIP revealed a large number of Nova-RNA interactions in 3’ UTRs, leading to the discovery that Nova regulates alternative polyadenylation in the brain. HITS-CLIP, therefore, provides a robust, unbiased means to identify functional protein-RNA interactions in vivo. This SuperSeries is composed of the SubSeries listed below.

2009-11-04 | GSE12965 | GEO

Integrative modeling defines the Nova splicing-regulatory network and its combinatorial controls: Exon array data

2010-08-04 | GSE22115 | GEO

Wild type vs. Nova2 KO mouse E14.5 cortex RNA

2010-07-07 | GSE22758 | GEO

RNAseq in E18.5 wild-type, Nova2-KO, and Nova1-KO mouse cortex and mid- and hind-brain

Project description:We sequenced mRNA from E18.5 mouse cortex (3 wild-type vs 3 Nova2-/- and 3 wild-type vs 3 Nova1-/-) and from E18.5 mouse mid- and hind-brain (3 wild-type vs 3 Nova1-/-) to compare gene expression level and alternative splicing events between wild-type and Nova mutant mice.

2016-05-26 | GSE69709 | GEO

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