Irg1l regulates neuromast size via metabolic reprogramming to promote supporting cell proliferation

One of the most basic principles in embryonic development is ensuring the proper size of tissues and organs to meet functional needs. So far, an endogenous metabolite regulating organ size has not been described. The current study highlights itaconate, the product of Irg1, in regulating zebrafish neuromast size. Single-cell transcriptomic sequencing analysis of enzymes catalyzing metabolic processes revealed that irg1l, a homolog of Irg1, is highly expressed in supporting cells of developing neuromast in zebrafish. Deficiency of irg1l reduced the size of the neuromast and caused auditory dysfunction. Conversely, overexpression of irg1l resulted in increased size due to excessive proliferation of supporting cells. Notably, 4-octyl itaconate (4-OI), an itaconate derivative, treatment recapitulates the phenotype of irg1l overexpression and increases the neuromast size. Finally, we revealed that the Irg1l/itaconate axis induces metabolic reprogramming to promote activation of the Yap, drive supporting cell proliferation, and enlarge neuromast size. These findings provide a novel insight into the role of metabolites in organ development.