Top affected gene functions in the PGR mutant.

20-carbon fatty acid-derived eicosanoids are versatile signaling oxylipins in mammals. In particular, a group of eicosanoids termed prostanoids are involved in multiple physiological processes, such as reproduction and immune responses. Although some eicosanoids such as prostaglandin E2 (PGE2) have been detected in some insect species, molecular mechanisms of eicosanoid synthesis and signal transduction in insects have not been thoroughly investigated. Our phylogenetic analysis indicated that, in clear contrast to the presence of numerous receptors for oxylipins and other lipid mediators in humans, the Drosophila genome only possesses a single ortholog of such receptors, which is homologous to human prostanoid receptors. This G protein-coupled receptor, named Prostaglandin Receptor or PGR, is activated by PGE2 and its isomer PGD2 in Drosophila S2 cells. PGR mutant flies die as pharate adults with insufficient tracheal development, which can be rescued by supplying high oxygen. Consistent with this, through a comprehensive mutagenesis approach, we identified a Drosophila PGE synthase whose mutants show similar pharate adult lethality with hypoxia responses. Drosophila thus has a highly simplified eicosanoid signaling pathway as compared to humans, and it may provide an ideal model system for investigating evolutionarily conserved aspects of eicosanoid signaling.

源自20碳脂肪酸的类二十烷酸（eicosanoids）是哺乳动物中功能多样的信号性氧脂素（oxylipins）。具体而言，被称为前列腺烷酸类（prostanoids）的一类类二十烷酸参与了包括生殖与免疫应答在内的多种生理过程。尽管已有研究在部分昆虫物种中检测到诸如前列腺素E2（PGE2）这类类二十烷酸，但昆虫体内类二十烷酸合成与信号转导的分子机制尚未得到充分研究。我们的系统发育分析显示，与人类体内存在大量氧脂素（oxylipins）及其他脂质介质受体的情况形成鲜明对比的是，果蝇（Drosophila）基因组中仅存在这类受体的一个同源基因，该基因与人类前列腺烷酸类受体具有同源性。这个被命名为前列腺素受体（Prostaglandin Receptor，简称PGR）的G蛋白偶联受体（G protein-coupled receptor），在果蝇S2细胞中可被PGE2及其异构体前列腺素D2（PGD2）激活。PGR突变体果蝇会以蛹后期成虫的形式死亡，其气管发育不全，该表型可通过高氧处理得到挽救。与此一致，我们通过全面诱变筛选的方法，鉴定出一种果蝇前列腺素E合酶（PGE synthase），其突变体同样表现出蛹后期成虫致死表型，并伴随缺氧应答特征。因此，与人类相比，果蝇体内的类二十烷酸信号通路极为简化，其可作为研究类二十烷酸信号通路演化保守性特征的理想模型系统。