Thermosensitive alternative splicing senses and mediates temperature adaptation in Drosophila
- Brandeis University, United States
- The Hebrew University of Jerusalem, Israel
Abstract
Circadian rhythms are generated by cyclic transcription, translation, and degradation of clock gene products, including timeless (tim), but how the circadian clock senses and adapts to temperature changes is not completely understood. Here we show that temperature dramatically changes the splicing pattern of tim in Drosophila. We found that at 18 °C, TIM levels are low due to the induction of two cold-specific isoforms: tim-cold and tim-short&cold. At 29 °C, another isoform, tim-medium, is upregulated. This isoform switching regulates the levels and activity of TIM as each isoform has a specific function. We found that tim-short&cold encodes a protein that rescues the behavioral defects of tim01 mutants and that flies in which tim-short&cold is abrogated have abnormal locomotor activity. In addition, miRNA-mediated control limits the expression of some of these isoforms. Finally, our data using minigenes suggest that tim alternative splicing might act as a thermometer for the circadian clock.
Data availability
Sequencing data have been deposited in GEO under accession codes GSE124134, 124135, 124141, 123142, 124200 and 124201.
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Small RNA seq from Ago1-IP of fly heads at different temperatures and circadian timepointsNCBI Gene Expression Omnibus, GSE124134.
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total mRNA seq from fly heads at different temperatures and circadian timepointsNCBI Gene Expression Omnibus, GSE124135.
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3' end RNA seq from fly heads at different temperatures and circadian timepointsNCBI Gene Expression Omnibus, GSE124141.
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Total RNA from different species fly headsNCBI Gene Expression Omnibus, GSE123142.
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3' end RNA seq from fly heads at different temperatures and circadian timepointsNCBI Gene Expression Omnibus, GSE124200.
Article and author information
Author details
Funding
National Institutes of Health (R01GM125859)
- Sebastian Kadener
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Mani Ramaswami, Trinity College Dublin, Ireland
Version history
- Received: December 21, 2018
- Accepted: November 7, 2019
- Accepted Manuscript published: November 8, 2019 (version 1)
- Version of Record published: December 3, 2019 (version 2)
Copyright
© 2019, Martin Anduaga 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.
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Thermosensitive alternative splicing senses and mediates temperature adaptation in Drosophila
eLife 8:e44642.
https://doi.org/10.7554/eLife.44642
Further reading
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- 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.
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