Cellular metabolism as a developmental regulator of microglial fate and function

Cellular metabolism affects all aspects of cell function and life. Classically, metabolism was thought to respond to the energy needs of a cell following commitment to a specific fate. Challenging this notion, growing evidence suggests that metabolism has an instructive role in determining cell fate through mitochondrial-nuclear crosstalk (1, 2). Here, we ask whether metabolism could provide the key to understanding development and function of microglia, the resident innate immune cells of the brain. This knowledge is urgently needed, as dysfunctional microglia contribute to a wide range of neurodevelopmental, neuropsychiatric and neurodegenerative diseases. Specifically, we will test the hypothesis that metabolic reprogramming drives critical transcriptional and epigenetic changes in microglia, leading to their differentiation and functional specialization in brain development. Our preliminary data show that changes in metabolism, coined ‘metabolic reprogramming’, are observed in developing microglia during embryogenesis. We will focus on two major microglial metabolic programs – aerobic glycolysis and oxidative phosphorylation (OXPHOS). Firstly, we will determine the spatio-temporal sequence of microglial metabolic, epigenetic, transcriptional and functional changes during embryonic development, as well as the key intrinsic and extrinsic environmental cues that trigger microglial metabolic reprogramming during development. Secondly, we will test whether switching the metabolic program is sufficient to direct microglial differentiation and function. To address this in vivo, we will use genetically encoded, light-controlled metabolic switches that enable non-invasive, precise temporal and spatial control of glycolysis and OXPHOS in living animals. Thirdly, we will define how metabolic reprogramming directs microglial fate, determining if metabolic reprogramming drives epigenetic modification and transcriptional states. This project will advance our fundamental understanding of how microglia attain different fates. The knowledge developed here will be immediately relevant to human disease. Novel molecular pathways controlling microglial fate will provide new avenues to reprogramme dysfunctional microglia in disease, and new targets for in vitro generation of microglia, which is an essential precursor for development of microglia replacement therapies. Our project will also develop novel experimental models enabling precise in vivo control of microglial metabolism, an advance that overcomes technical challenges currently faced in investigating energy metabolism in health and disease. Our application of optogenetic tools to understand microglial development and function represents a world first. These models will open new avenues of research to understand disorders characterized by microglial metabolic dysfunction. More broadly, the proposed experiments will help conceptually re-define mitochondria as mediators of cell fate, in addition to their textbook role as suppliers of energy.