Social interaction-induced activation of RNA splicing in the amygdala of microbiome-deficient mice
- University College Cork, Ireland
Abstract
Social behaviour is regulated by activity of host-associated microbiota across multiple species. However, the molecular mechanisms mediating this relationship remain elusive. We therefore determined the dynamic, stimulus-dependent transcriptional regulation of germ-free (GF) and GF mice colonised post weaning (exGF) in the amygdala, a brain region critically involved in regulating social interaction. In GF mice the dynamic response seen in controls was attenuated and replaced by a marked increase in expression of splicing factors and alternative exon usage in GF mice upon stimulation, which was even more pronounced in exGF mice. In conclusion, we demonstrate a molecular basis for how the host microbiome is crucial for a normal behavioural response during social interaction. Our data further suggest that social behaviour is correlated with the gene-expression response in the amygdala, established during neurodevelopment as a result of host-microbe interactions. Our findings may help toward understanding neurodevelopmental events leading to social behaviour dysregulation, such as those found in autism spectrum disorders (ASDs).
Data availability
The data discussed in this publication have been deposited in NCBI's Gene Expression Omnibus [86] and are accessible through GEO Series accession number GSE114702 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE114702
-
Data from: Social interaction-induced activation of RNA splicing in the amygdala of microbiome-deficient micePublicly available at the NCBI Gene Expression Omnibus (accession no: GSE114702).
Article and author information
Author details
Funding
Science Foundation Ireland (12/RC/2273)
- Fergus Shanahan
- Gerard Clarke
- Marcus J Claesson
- Timothy G Dinan
- John F Cryan
Irish Research Council (GOIPD/2014/355)
- Roman M Stilling
- John F Cryan
Irish Health Board
- Timothy G Dinan
- John F Cryan
NARSAD (20771)
- Gerard Clarke
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Elaine Y Hsiao, California Institute of Technology, United States
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations provided by Laboratory Animal Science and Training (LAST) Ireland. All of the animals were handled according to institutional protocols approved by the Animal Ethics Experimentation Committee (AEEC) of University College Cork (#2015/014) and the Health Products Regulatory Authority (HPRA) Ireland (#AE19130/P023). Every effort was made to minimize suffering and animals were killed humanely.
Version history
- Received: October 24, 2017
- Accepted: May 15, 2018
- Accepted Manuscript published: May 29, 2018 (version 1)
- Version of Record published: June 11, 2018 (version 2)
Copyright
© 2018, Stilling et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 4,887
- views
-
- 572
- downloads
-
- 70
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Social interaction-induced activation of RNA splicing in the amygdala of microbiome-deficient mice
eLife 7:e33070.
https://doi.org/10.7554/eLife.33070
Further reading
-
Mice raised in sterile environments are less social.
-
- Cell Biology
- Neuroscience
Alternative RNA splicing is an essential and dynamic process in neuronal differentiation and synapse maturation, and dysregulation of this process has been associated with neurodegenerative diseases. Recent studies have revealed the importance of RNA-binding proteins in the regulation of neuronal splicing programs. However, the molecular mechanisms involved in the control of these splicing regulators are still unclear. Here, we show that KIS, a kinase upregulated in the developmental brain, imposes a genome-wide alteration in exon usage during neuronal differentiation in mice. KIS contains a protein-recognition domain common to spliceosomal components and phosphorylates PTBP2, counteracting the role of this splicing factor in exon exclusion. At the molecular level, phosphorylation of unstructured domains within PTBP2 causes its dissociation from two co-regulators, Matrin3 and hnRNPM, and hinders the RNA-binding capability of the complex. Furthermore, KIS and PTBP2 display strong and opposing functional interactions in synaptic spine emergence and maturation. Taken together, our data uncover a post-translational control of splicing regulators that link transcriptional and alternative exon usage programs in neuronal development.
