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Immunoresponsive gene 1 like/itaconate axis promotes neuromast size via metabolic reprogramming to induce Yap signaling

ABSTRACT: The organ size control and tissue homeostasis maintenance are vital in the formation of vertebrate sensory organs, which are tightly regulated. Here, we identify a metabolic regulatory axis, Irg1l, a zebrafish homologue of the mammalian mitochondrial enzyme immunoresponsive gene 1, and its product itaconate in neuromast development. It was demonstrated that irg1l was found to be highly and specifically expressed in supporting cells of developing neuromast, and decreased along the hair cell trajectory. Loss-of-function of irg1l caused neuromast size reduction and auditory dysfunction. Conversely, gain-of-function of irg1l increased the neuromast size. We found that excessive proliferation of supporting cells results in the larger neuromast. Notably, 4-octyl itaconate (4-OI), an itaconate derivative, recapitulates the phenotype of irg1l overexpression and increases the neuromast size. Mechanistically, Irg1l and itaconate induce succinate accumulation, which could lead to disruptions of the TCA cycle. It was confirmed by transcriptome sequencing and metabolic pathway inhibitor treatment. Inhibiting and activating YAP, respectively, can rescue the up- or down-regulation of Irg1l/itaconate-induced phenotypes, suggesting that YAP signaling acts downstream of metabolic reprograming induced by irg1l/ITA axis. Collectively, these results provide a novel insight into the role of metabolic signaling and its transduction during sensory organ development. Targeting this metabolic regulatory pathway within supporting cells may prove useful in further regulating sensory hair cell development and regeneration.

ORGANISM(S): Danio rerio

PROVIDER: GSE264562 | GEO | 2025/10/21

REPOSITORIES: GEO

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