Estrogen-related receptor is required in adult Drosophila females for germline stem cell maintenance.

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.