Journal article
Overlapping Activities of Two Neuronal Splicing Factors Switch the GABA Effect from Excitatory to Inhibitory by Regulating REST
Cell reports (Cambridge), Vol.27(3), pp.860-871.e8
04/16/2019
DOI: 10.1016/j.celrep.2019.03.072
PMCID: PMC6556397
PMID: 30995482
Abstract
A truncating mutation in the mouse Srrm4 gene, which encodes a neuronal splicing factor, causes alternative splicing defects selectively in the ear. The mechanism by which splicing is preserved in the brain of these mice is not known. Here, we show that SRRM3 limits the Srrm4 mutation-associated defects to the ear and that, in cortical neurons, overlapping SRRM3-SRRM4 activity regulates the development of interneuronal inhibition. In vitro, SRRM3 and SRRM4 regulate the same splicing events, but a mutation in mouse Srrm3 causes tremors and mild defects in neuronal alternative splicing, demonstrating unique SRRM3 roles in vivo. Mice harboring mutations in both Srrm3 and Srrm4 die neonatally and exhibit severe splicing defects. In these mice, splicing alterations prevent inactivation of the gene repressor REST, which maintains immature excitatory GABAergic neurotransmission by repressing K-Cl cotransporter 2. Thus, our data reveal that SRRM3 and SRRM4 act redundantly to regulate GABAergic neurotransmission by inactivating REST.
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•SRRM3 is a neuronal regulator of alternative splicing required for motor coordination•SRRM3 and SRRM4 regulate neuronal splicing of overlapping groups of alternative exons•SRRM3-SRRM4 activity elevates Kcc2 expression by inactivating the gene repressor REST•SRRM3-SRRM4 switch the GABA effect from excitatory to inhibitory by upregulating Kcc2
Nakano et al. report that the paralogous proteins SRRM3 and SRRM4 regulate the alternative splicing of overlapping groups of exons in the CNS and that the SRRM3-SRRM4-regulated splicing alterations change GABAergic neurotransmission from excitatory to inhibitory during development by inactivating the gene repressor REST and derepressing its target gene Kcc2.
Details
- Title: Subtitle
- Overlapping Activities of Two Neuronal Splicing Factors Switch the GABA Effect from Excitatory to Inhibitory by Regulating REST
- Creators
- Yoko Nakano - Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USASusan Wiechert - Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USABotond Bánfi - Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA
- Resource Type
- Journal article
- Publication Details
- Cell reports (Cambridge), Vol.27(3), pp.860-871.e8
- Publisher
- Elsevier Inc
- DOI
- 10.1016/j.celrep.2019.03.072
- PMID
- 30995482
- PMCID
- PMC6556397
- ISSN
- 2211-1247
- eISSN
- 2211-1247
- Grant note
- name: University of Iowa Carver College of Medicine; name: NIDCD/NIH, award: R01DC010152, R01DC014953
- Language
- English
- Date published
- 04/16/2019
- Academic Unit
- Anatomy and Cell Biology; Otolaryngology; Internal Medicine
- Record Identifier
- 9984025420102771
Metrics
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