Olfactory Control of Drosophila Blood-Progenitor Homeostasis and Development via Redox Regulation

Abstract

Akin to mammalian common myeloid progenitors, blood-progenitor cells of Drosophila maintain elevated levels of reactive oxygen species (ROS) whose homeostasis is necessary for their development. While physiological levels of ROS sensitize progenitor cells towards differentiation, its excessive production leads to oxidative stress and loss of progenitor homeostasis. However, mechanisms underlying redox homeostasis during blood progenitor development are not clear. The current thesis work aims to understand the mechanisms controlling blood-progenitor development via redox regulation and presents the developmental role of olfaction-derived GABA catabolism in blood progenitor redox homeostasis. GABA metabolism is linked to limiting pyruvate's entry into the TCA cycle and restricts TCA-derived precocious ROS production. Additionally, GABA catabolism promotes pyruvate cycling to generate serine and cysteine, which enables the blood progenitor cells with a capacity to generate glutathione, a potent antioxidant. Together, this dual modality keeps ROS levels in the blood progenitor cells in check and is important for homeostatic lymph gland development. Overall, this work demonstrates the metabolic requirement of odor sensing and GABA in regulating redox homeostasis during Drosophila myeloid progenitor development, the relevance of which may be broadly conserved.