Abstract
Similar to many diurnal animals, Drosophila melanogaster exhibits a mid-day siesta that is more robust as temperature increases, an adaptive response that aims to minimize the deleterious effects from exposure to heat. This temperature-dependent plasticity in mid-day sleep levels is partly based on the thermal sensitive splicing of an intron in the 3′ untranslated region (UTR) of the circadian clock gene termed period (per). In this study, we evaluated a possible role for the serine/arginine-rich (SR) splicing factors in the regulation of dmpi8 splicing efficiency and mid-day siesta. Using a Drosophila cell culture assay we show that B52/SRp55 increases dmpi8 splicing efficiency, whereas other SR proteins have little to no effect. The magnitude of the stimulatory effect of B52 on dmpi8 splicing efficiency is modulated by natural variation in single nucleotide polymorphisms (SNPs) in the per 3′ UTR that correlate with B52 binding levels. Down-regulating B52 expression in clock neurons increases mid-day siesta and reduces dmpi8 splicing efficiency. Our results establish a novel role for SR proteins in sleep and suggest that polymorphisms in the per 3′ UTR contribute to natural variation in sleep behavior by modulating the binding efficiencies of SR proteins.
Highlights
Wake-sleep cycles in animals are governed by networks of cell-based circadian (≅24 hr) ‘clocks’ or pacemakers located in the brain[1,2]
Weak 5′ and 3′ ss are the basis for the thermal sensitivity underlying dmpi[8] splicing efficiency, analysis of natural populations of D. melanogaster derived from different continents identified several single nucleotide polymorphisms (SNPs) in the dper 3′ untranslated region (UTR) that can modulate dmpi[8] splicing efficiency and mid-day sleep[13,14]
Our findings identify B52 as a novel regulator of sleep/arousal in Drosophila, and suggest that the interplay between cis-acting SNPs and trans-acting SR proteins contributes to natural variation in sleep behavior
Summary
Wake-sleep cycles in animals are governed by networks of cell-based circadian (≅24 hr) ‘clocks’ or pacemakers located in the brain[1,2]. Suppressing mid-day activity with a concomitant shift towards the cooler dusk hours on warm days minimizes the risks associated with exposure to the hot mid-day sun We showed that this temperature-dependent behavioral adaptation is partially controlled by thermosensitive splicing of a 3′-terminal intron from the Drosophila melanogaster period (dper) transcript[5,7], which is a key circadian clock factor known for encoding species-specific circadian behavioral programs in Drosophila[7,8,9,10]. Using a simplified Drosophila cell culture system[7,14], we show that B52/SRp55 enhances the splicing efficiency of dmpi[8], with larger effects in the VT1.1 context compared to that of VT1.2 In agreement with these results, cross-linking and immunoprecipitation studies revealed that B52 binds transcripts containing either the VT1.1 or VT1.2 versions of the dper 3′ UTR, binding levels are higher for transcripts containing the VT1.1 variant. Our findings identify B52 as a novel regulator of sleep/arousal in Drosophila, and suggest that the interplay between cis-acting SNPs and trans-acting SR proteins contributes to natural variation in sleep behavior
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