The progesterone antagonist mifepristone/RU486 blocks the negative effect on life span caused by mating in female Drosophila

Landis, Gary N.; Salomon, Matthew P.; Keroles, Daniel; Brookes, Nicholas; Sekimura, Troy; Tower, John

doi:10.18632/aging.100721

Cited by 46 publications

(83 citation statements)

References 49 publications

(83 reference statements)

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“…Three day old flies were selected to represent young [1, 19], and 60 day old flies to represent the old time point, because at 60 days >80% of the population had survived, thereby reducing potential selection bias and cohort effects [20]. Virgin male and female flies were examined to avoid any potential confounding effects of mating on stress responses [21]. …”

Section: Resultsmentioning

confidence: 99%

“…qPCR analysis confirmed both Lon RA and Lon RC splice forms to be present in males and females in similar ratio (Figure S2D). In addition, re-analysis of whole-body transcriptome of 12 day-old virgin females, mated females, and males found no sex-related variation in expression of Lon exons (Figure S2E) [21]. Therefore the 60kD and 50kD Lon protein isoforms do not appear to result from alternative splice variants of lon mRNA.…”

Section: Resultsmentioning

confidence: 99%

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The Mitochondrial Lon Protease Is Required for Age-Specific and Sex-Specific Adaptation to Oxidative Stress

et al. 2017

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Summary Multiple human diseases involving chronic oxidative stress show a significant sex bias, including neurodegenerative diseases, cancer, immune dysfunction, diabetes, and cardiovascular disease. However a possible molecular mechanism for the sex-bias in physiological adaptation to oxidative stress remains unclear. Here we report that Drosophila melanogaster females but not males adapt to hydrogen peroxide stress, whereas males but not females adapt to paraquat (superoxide) stress. Stress adaptation in each sex required the conserved mitochondrial Lon protease and was associated with sex-specific expression of Lon protein isoforms and proteolytic activity. Adaptation to oxidative stress was lost with age in both sexes. Transgenic expression of transformer gene during development transformed chromosomal males into pseudo-females, and conferred the female-specific pattern of Lon isoform expression, Lon proteolytic activity induction and H2O2 stress adaptation; these effects were also observed using adult-specific transformation. Conversely, knockdown of transformer in chromosomal females eliminated the female-specific Lon isoform expression, Lon proteolytic activity induction and H2O2 stress adaptation, and produced the male-specific paraquat (superoxide) stress adaptation. Sex-specific expression of alternative Lon isoforms was also observed in mouse tissues. The results develop Drosophila melanogaster as a model for sex-specific stress adaptation regulated by the Lon protease, with potential implications for understanding sexual-dimorphism in human disease.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

The Mitochondrial Lon Protease Is Required for Age-Specific and Sex-Specific Adaptation to Oxidative Stress

et al. 2017

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“…Several genes associated with reproduction were significant for AI in mated flies only, including Arpc1, CG10433, CG17919, fry, heph, Sec5, Cg25C, and Shark. Mating has been shown to reduce life span (Chapman et al 1995;Flatt 2011;Landis et al 2015) and several genes reported to affect life span were also significant for AI in mated flies only (a-Man-Ia, bmm, mt:ATPase6, sNPF, and sm). Postmating immunity is also compromised in female fruit flies (reviewed by Peng et al 2005;Lawniczak et al 2007;McGraw et al 2008) and the genes CG10433, CG17652, CG17919, Gs1l, a-Man-Ia, mtd, Sec5, and Shark are involved in processes such as apoptosis, phagocytosis, and general immune responses.…”

Section: Environmental Effects On Allelic Imbalancementioning

confidence: 99%

“…In addition, phototransduction (P = 0.004142, 8 genes), detection of light stimulus (P = 0.00949, 8 genes), response to light stimulus (P = 0.017, 11 genes), and detection of visible light (P = 0.046, 6 genes) were also enriched. Phototransduction genes are known to be altered by mating in Drosophila (Gioti et al 2012;Landis et al 2015).…”

Section: Cis-and Trans-effectsmentioning

confidence: 99%

“…Finally, ps is spliced sex specifically (Telonis-Scott et al 2009) and is a splicing factor (Seshaiah et al 2001) and Vmat is involved in transmembrane transport as a splice variant that is involved in dopamine, serotonin, and octopamine transport (Greer et al 2005). Both dopamine signaling and octopamine signaling are implicated in mediating the postmating response (Rezaval et al 2014;Landis et al 2015). Figure 6 The distribution of R 2 for the regression Y ij = m + C i + T i + C i 3 T i , where Y isû; C i is the estimate of cis, and T i is trans for line i for each exon j. R 2 is an estimate of the contribution of cis-interactions, trans-interactions, and cis-by trans-interactions to AI.…”

Section: Cis-and Trans-effectsmentioning

confidence: 99%

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Buffering of Genetic Regulatory Networks in Drosophila melanogaster

et al. 2016

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Regulatory variation in gene expression can be described by cis-and trans-genetic components. Here we used RNA-seq data from a population panel of Drosophila melanogaster test crosses to compare allelic imbalance (AI) in female head tissue between mated and virgin flies, an environmental change known to affect transcription. Indeed, 3048 exons (1610 genes) are differentially expressed in this study. A Bayesian model for AI, with an intersection test, controls type I error. There are 200 genes with AI exclusively in mated or virgin flies, indicating an environmental component of expression regulation. On average 34% of genes within a cross and 54% of all genes show evidence for genetic regulation of transcription. Nearly all differentially regulated genes are affected in cis, with an average of 63% of expression variation explained by the cis-effects. Trans-effects explain 8% of the variance in AI on average and the interaction between cis and trans explains an average of 11% of the total variance in AI. In both environments cis-and trans-effects are compensatory in their overall effect, with a negative association between cis-and trans-effects in 85% of the exons examined. We hypothesize that the gene expression level perturbed by cis-regulatory mutations is compensated through trans-regulatory mechanisms, e. g., trans and cis by trans-factors buffering cis-mutations. In addition, when AI is detected in both environments, cis-mated, cis-virgin, and trans-mated-trans-virgin estimates are highly concordant with 99% of all exons positively correlated with a median correlation of 0.83 for cis and 0.95 for trans. We conclude that the gene regulatory networks (GRNs) are robust and that trans-buffering explains robustness.

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The progesterone antagonist mifepristone/RU486 blocks the negative effect on life span caused by mating in female Drosophila

Cited by 46 publications

References 49 publications

The Mitochondrial Lon Protease Is Required for Age-Specific and Sex-Specific Adaptation to Oxidative Stress

The Mitochondrial Lon Protease Is Required for Age-Specific and Sex-Specific Adaptation to Oxidative Stress

Buffering of Genetic Regulatory Networks in Drosophila melanogaster

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