Zike Anna B, Abel Madison G, Fleck Sophie A, DeWitt Emily D, Weaver Lesley N
Department of Biology, Indiana University, Bloomington, IN, 47405, USA.
Department of Biology, Indiana University, Bloomington, IN, 47405, USA.
Dev Biol. 2025 Aug;524:132-143. doi: 10.1016/j.ydbio.2025.05.005. Epub 2025 May 8.
Adult tissue function is dependent on intrinsic factors that mediate stem cell self-renewal and proliferation in response to changes in physiology and the environment. The estrogen-related receptor (ERR) subfamily of orphan nuclear receptors are major transcriptional regulators of metabolism and animal physiology. In mammals, ERRs (NR3B1, NR3B2, NR3B3) have roles in regulating mitochondrial biosynthesis, lipid metabolism, as well as stem cell maintenance. The sole Drosophila ERR ortholog promotes larval growth by establishing a metabolic state during the latter half of embryogenesis. In addition, ERR is required in adult Drosophila males to coordinate glycolytic metabolism with lipid synthesis and within the testis to regulate spermatogenesis gene expression and fertility. Despite extensive work characterizing the role of ERR in Drosophila metabolism, whether ERR has a conserved requirement in regulating stem cell behavior has been understudied. To determine whether ERR regulates stem cell activity in Drosophila, we used the established adult female germline stem cell (GSC) lineage as a model. We found that whole-body ERR knockout in adult females using conditional heat shock-driven FLP-FRT recombination significantly decreases GSC number and glycolytic enzyme expression in GSCs. In addition, we found that ERR activity is required cell-autonomously in the adult female germline for maintenance of GSCs; whereas ERR regulation of GSCs is independent of its activity in adult female adipocytes. Our results highlight an ancient and conserved role for ERRs in the regulation of stem cell self-renewal.
成体组织功能依赖于内在因素，这些因素介导干细胞自我更新和增殖，以响应生理和环境变化。孤儿核受体的雌激素相关受体（ERR）亚家族是代谢和动物生理学的主要转录调节因子。在哺乳动物中，ERRs（NR3B1、NR3B2、NR3B3）在调节线粒体生物合成、脂质代谢以及干细胞维持方面发挥作用。果蝇唯一的ERR直系同源物通过在胚胎发育后半期建立代谢状态来促进幼虫生长。此外，成年果蝇雄性需要ERR来协调糖酵解代谢与脂质合成，并且在睾丸内调节精子发生基因表达和生育能力。尽管在表征ERR在果蝇代谢中的作用方面进行了大量工作，但ERR在调节干细胞行为方面是否具有保守需求尚未得到充分研究。为了确定ERR是否调节果蝇中的干细胞活性，我们使用已建立的成年雌性生殖系干细胞（GSC）谱系作为模型。我们发现，使用条件性热休克驱动的FLP - FRT重组在成年雌性中进行全身ERR基因敲除会显著降低GSC数量和GSCs中的糖酵解酶表达。此外，我们发现ERR活性在成年雌性生殖系中对GSCs的维持是细胞自主必需的；而ERR对GSCs的调节独立于其在成年雌性脂肪细胞中的活性。我们的结果突出了ERRs在调节干细胞自我更新方面古老而保守的作用。
