Youchen Guan, Yong Yu, Shihong Max Gao, Lang Ding, Qian Zhao, Meng Wang
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Through genetic analysis, we discovered that two Caenorhabditis elegans homologs of SLC29A transporters, Equilibrative Nucleoside Transporter ENT-1 and ENT-2, act in the germline and the intestine, respectively, to regulate reproduction. Their knockdown synergistically results in sterility. Further single-cell transcriptomic and targeted metabolomic profiling revealed that the ENT double knockdown specifically affects genes in the purine biosynthesis pathway and reduces the ratio of guanosine to adenosine levels. Importantly, guanosine supplementation into the body cavity/pseudocoelom through microinjection rescued the sterility caused by the ENT double knockdown, whereas adenosine microinjection had no effect. Together, these studies support guanosine as a rate limiting factor in the control of reproduction, uncover the previously unknown nucleoside/nucleotide communication between the soma and the germline essential for reproductive success, and highlight the significance of SLC-mediated cell-nonautonomous metabolite coordination in regulating organism physiology.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"75 1","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Cross-Tissue Coordination between SLC Nucleoside Transporters Regulates Reproduction in Caenorhabditis elegans\",\"authors\":\"Youchen Guan, Yong Yu, Shihong Max Gao, Lang Ding, Qian Zhao, Meng Wang\",\"doi\":\"10.1101/2024.09.12.612591\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Metabolism is fundamental to organism physiology and pathology. From the intricate network of metabolic reactions, diverse chemical molecules, collectively termed as metabolites, are produced. In multicellular organisms, metabolite communication between different tissues is vital for maintaining homeostasis and adaptation. However, the molecular mechanisms mediating these metabolite communications remain poorly understood. Here, we focus on nucleosides and nucleotides, essential metabolites involved in multiple cellular processes, and report the pivotal role of the SLC29A family of transporters in mediating nucleoside coordination between the soma and the germline. Through genetic analysis, we discovered that two Caenorhabditis elegans homologs of SLC29A transporters, Equilibrative Nucleoside Transporter ENT-1 and ENT-2, act in the germline and the intestine, respectively, to regulate reproduction. Their knockdown synergistically results in sterility. Further single-cell transcriptomic and targeted metabolomic profiling revealed that the ENT double knockdown specifically affects genes in the purine biosynthesis pathway and reduces the ratio of guanosine to adenosine levels. Importantly, guanosine supplementation into the body cavity/pseudocoelom through microinjection rescued the sterility caused by the ENT double knockdown, whereas adenosine microinjection had no effect. 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引用次数: 0
摘要
新陈代谢是生物体生理和病理的基础。在错综复杂的代谢反应网络中,会产生各种化学分子,统称为代谢物。在多细胞生物体中,不同组织之间的代谢物交流对于维持平衡和适应至关重要。然而,人们对介导这些代谢物交流的分子机制仍然知之甚少。在这里,我们重点研究了核苷酸和核苷酸这种参与多种细胞过程的重要代谢物,并报告了 SLC29A 转运体家族在介导核苷酸在体细胞和生殖细胞之间的协调中的关键作用。通过遗传分析,我们发现草履虫的两个SLC29A转运体同源物--平衡核苷转运体ENT-1和ENT-2--分别在生殖细胞和肠道中调节生殖。敲除它们会协同导致不育。进一步的单细胞转录组和靶向代谢组分析表明,ENT双基因敲除特异性地影响了嘌呤生物合成途径中的基因,并降低了鸟苷与腺苷的比例。重要的是,通过微量注射向体腔/假肠腔补充鸟苷能挽救 ENT 双基因敲除导致的不育,而微量注射腺苷则没有效果。总之,这些研究支持鸟苷是控制繁殖的限速因子,揭示了之前未知的、对繁殖成功至关重要的体细胞和生殖细胞之间的核苷/核苷酸交流,并强调了 SLC 介导的细胞自主代谢物协调在调节生物体生理方面的重要意义。
Cross-Tissue Coordination between SLC Nucleoside Transporters Regulates Reproduction in Caenorhabditis elegans
Metabolism is fundamental to organism physiology and pathology. From the intricate network of metabolic reactions, diverse chemical molecules, collectively termed as metabolites, are produced. In multicellular organisms, metabolite communication between different tissues is vital for maintaining homeostasis and adaptation. However, the molecular mechanisms mediating these metabolite communications remain poorly understood. Here, we focus on nucleosides and nucleotides, essential metabolites involved in multiple cellular processes, and report the pivotal role of the SLC29A family of transporters in mediating nucleoside coordination between the soma and the germline. Through genetic analysis, we discovered that two Caenorhabditis elegans homologs of SLC29A transporters, Equilibrative Nucleoside Transporter ENT-1 and ENT-2, act in the germline and the intestine, respectively, to regulate reproduction. Their knockdown synergistically results in sterility. Further single-cell transcriptomic and targeted metabolomic profiling revealed that the ENT double knockdown specifically affects genes in the purine biosynthesis pathway and reduces the ratio of guanosine to adenosine levels. Importantly, guanosine supplementation into the body cavity/pseudocoelom through microinjection rescued the sterility caused by the ENT double knockdown, whereas adenosine microinjection had no effect. Together, these studies support guanosine as a rate limiting factor in the control of reproduction, uncover the previously unknown nucleoside/nucleotide communication between the soma and the germline essential for reproductive success, and highlight the significance of SLC-mediated cell-nonautonomous metabolite coordination in regulating organism physiology.