Mutation of the GDP-Fucose Biosynthesis Gene gmds Increases Hair Cell Number and Neuromast Regenerative Capacity in Zebrafish

Hearing loss affects millions and is often caused by irreversible damage to mechanosensory hair cells. Humans and other mammals lack the capacity to regenerate damaged hair cells; however zebrafish, <i>Danio rerio</i>, can regenerate hair cells that are present in the ear and mechanosensory neuromasts, making this animal an ideal model for understanding hair cell regenerative mechanisms. This study investigates the role of the GDP-fucose biosynthesis gene <i>GDP-mannose 4,6-dehydratase</i> (<i>gmds</i>) in regulating neuromast hair cell regeneration in zebrafish. Fucosylation is required for Notch signalling, a critical negative regulator of hair cell regeneration, and we therefore hypothesized that loss of <i>gmds</i> function would enhance hair cell regeneration. We demonstrate increased hair cell number in <i>gmds</i> mutants, and increased hair cell number following chemical ablation of hair cells with neomycin. Additionally, <i>gmds</i> mutants exhibited accelerated neuromast and hair cell regeneration, achieving complete restoration faster than wild-type siblings. Pharmacological inhibition of Notch signalling further enhanced hair cell regeneration in wild-type siblings but less so in <i>gmds</i> mutants, indicating that Notch signalling may partially regulate hair cell regeneration downstream of <i>gmds</i>. These findings highlight the importance of GDP-fucose biosynthesis in regulating hair cell number and regeneration, likely partially dependent on Notch signalling.