Estrogen-Related Receptor is Required in Adult Drosophila Females for Germline Stem Cell Maintenance

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 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 of 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 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 ERRs in the regulation of stem cell self-renewal. SUMMARYTissue function and regeneration are dependent on stem cell populations, which relies on the coordination of energy homeostasis between multiple tissues within an organism. Zike et al report that the estrogen-related receptor (ERR) is required in adult Drosophila females to maintain germline stem cell number in the ovary to promote egg production. Furthermore, ERR regulation of stem cell maintenance is dependent on its cell autonomous role in the germline, but not through adipocyte-specific ERR activity. These findings demonstrate that the sole Drosophila ERR has a conserved role in regulating stem cell lineages (similar as the mammalian ERR{beta} ortholog) and can be used as a model to understand regulation of stem cell lineages as well as metabolism.