Zike Anna B, Abel Madison G, Fleck Sophie A, DeWitt Emily D, Weaver Lesley N
Department of Biology, Indiana University, Bloomington, IN 47405, USA.
bioRxiv. 2025 Jan 29:2025.01.29.635514. doi: 10.1101/2025.01.29.635514.
Stem cell self-renewal and proper tissue function rely on conserved metabolic regulators to balance energy production with inter-organ metabolic trafficking. The estrogen-related receptor (ERR) subfamily of orphan nuclear receptors are major transcriptional regulators of metabolism. In mammals, ERRs have roles in regulating mitochondrial biosynthesis, lipid metabolism, as well as stem cell maintenance. The sole ortholog promotes larval growth by establishing a metabolic state during the latter half of embryogenesis. In addition, is required in adult males to coordinate glycolytic metabolism with lipid synthesis and within the testis to regulate spermatogenesis gene expression and fertility. Despite extensive work characterizing of the role of in metabolism, whether has a conserved requirement in regulating stem cell behavior has been understudied. To determine whether ERR regulates stem cell activity in , we used the established adult female germline stem cell (GSC) lineage as a model. We found that whole-body knockout in adult females using conditional heat shock-driven FLP-FRT recombination significantly reduces egg production and decreases GSC number. 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 in the regulation of stem cell self-renewal.
干细胞的自我更新和正常的组织功能依赖于保守的代谢调节因子，以平衡能量产生与器官间的代谢运输。孤儿核受体的雌激素相关受体（ERR）亚家族是代谢的主要转录调节因子。在哺乳动物中，ERRs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。唯一的直系同源物通过在胚胎发育后半期建立一种代谢状态来促进幼虫生长。此外，成年雄性需要它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。尽管已经有大量工作描述了它在代谢中的作用，但它在调节干细胞行为方面是否具有保守需求却鲜有研究。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重组在成年雌性果蝇中进行全身敲除，会显著降低产卵量并减少GSC数量。此外，我们发现ERR活性在成年雌性生殖系中对GSCs的维持具有细胞自主性需求；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ERR在调节干细胞自我更新方面古老而保守的作用。
