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      Drosophila PSI controls circadian period and the phase of circadian behavior under temperature cycle via tim splicing

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          Abstract

          The Drosophila circadian pacemaker consists of transcriptional feedback loops subjected to post-transcriptional and post-translational regulation. While post-translational regulatory mechanisms have been studied in detail, much less is known about circadian post-transcriptional control. Thus, we targeted 364 RNA binding and RNA associated proteins with RNA interference. Among the 43 hits we identified was the alternative splicing regulator P-element somatic inhibitor (PSI). PSI regulates the thermosensitive alternative splicing of timeless ( tim), promoting splicing events favored at warm temperature over those increased at cold temperature. Psi downregulation shortens the period of circadian rhythms and advances the phase of circadian behavior under temperature cycle. Interestingly, both phenotypes were suppressed in flies that could produce TIM proteins only from a transgene that cannot form the thermosensitive splicing isoforms. Therefore, we conclude that PSI regulates the period of Drosophila circadian rhythms and circadian behavior phase during temperature cycling through its modulation of the tim splicing pattern.

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          Most cited references57

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          A pdf neuropeptide gene mutation and ablation of PDF neurons each cause severe abnormalities of behavioral circadian rhythms in Drosophila.

          The mechanisms by which circadian pacemaker systems transmit timing information to control behavior are largely unknown. Here, we define two critical features of that mechanism in Drosophila. We first describe animals mutant for the pdf neuropeptide gene, which is expressed by most of the candidate pacemakers (LNv neurons). Next, we describe animals in which pdf neurons were selectively ablated. Both sets of animals produced similar behavioral phenotypes. Both sets entrained to light, but both were largely arrhythmic under constant conditions. A minority of each pdf variant exhibited weak to moderate free-running rhythmicity. These results confirm the assignment of LNv neurons as the principal circadian pacemakers controlling daily locomotion in Drosophila. They also implicate PDF as the principal circadian transmitter.
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            RBPDB: a database of RNA-binding specificities

            The RNA-Binding Protein DataBase (RBPDB) is a collection of experimental observations of RNA-binding sites, both in vitro and in vivo, manually curated from primary literature. To build RBPDB, we performed a literature search for experimental binding data for all RNA-binding proteins (RBPs) with known RNA-binding domains in four metazoan species (human, mouse, fly and worm). In total, RPBDB contains binding data on 272 RBPs, including 71 that have motifs in position weight matrix format, and 36 sets of sequences of in vivo-bound transcripts from immunoprecipitation experiments. The database is accessible by a web interface which allows browsing by domain or by organism, searching and export of records, and bulk data downloads. Users can also use RBPDB to scan sequences for RBP-binding sites. RBPDB is freely available, without registration at http://rbpdb.ccbr.utoronto.ca/.
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              CRY, a Drosophila clock and light-regulated cryptochrome, is a major contributor to circadian rhythm resetting and photosensitivity.

              Light is a major environmental signal for circadian rhythms. We have identified and analyzed cry, a novel Drosophila cryptochrome gene. All characterized family members are directly photosensitive and include plant blue light photoreceptors. We show that cry transcription is under circadian regulation, influenced by the Drosophila clock genes period, timeless, Clock, and cycle. We also show that cry protein levels are dramatically affected by light exposure. Importantly, circadian photosensitivity is increased in a cry-overexpressing strain. These physiological and genetic data therefore link a specific photoreceptor molecule to circadian rhythmicity. Taken together with the data in the accompanying paper, we propose that CRY is a major Drosophila photoreceptor dedicated to the resetting of circadian rhythms.
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                Author and article information

                Contributors
                Role: Reviewing Editor
                Role: Senior Editor
                Journal
                eLife
                Elife
                eLife
                eLife
                eLife Sciences Publications, Ltd
                2050-084X
                08 November 2019
                2019
                : 8
                : e50063
                Affiliations
                [1 ]deptDepartment of Neurobiology University of Massachusetts Medical School WorcesterUnited States
                [2 ]Hebrew University of Jerusalem JerusalemIsrael
                [3 ]Brandeis University WalthamUnited States
                Trinity College Dublin Ireland
                Emory University United States
                Trinity College Dublin Ireland
                Author information
                https://orcid.org/0000-0001-7635-7338
                http://orcid.org/0000-0003-0080-5987
                https://orcid.org/0000-0001-5176-6565
                Article
                50063
                10.7554/eLife.50063
                6890465
                31702555
                312ae8a1-951c-47bd-8363-6384671118d0
                © 2019, Foley et al

                This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

                History
                : 10 July 2019
                : 07 November 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100000057, National Institute of General Medical Sciences;
                Award ID: 1R35GM118087
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100000057, National Institute of General Medical Sciences;
                Award ID: 1R01GM125859
                Award Recipient :
                The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
                Categories
                Research Article
                Neuroscience
                Custom metadata
                A screen targeting RNA-associated proteins reveals that PSI regulates timeless alternative splicing and thus controls the period of Drosophila circadian behavior and its phase under temperature cycles.

                Life sciences
                circadian rhythms,rna binding proteins,alternative splicing,timeless,d. melanogaster
                Life sciences
                circadian rhythms, rna binding proteins, alternative splicing, timeless, d. melanogaster

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