Pontocerebellar hypoplasia type 6 is a severe childhood brain disorder caused by defects in genes important for mitochondrial function. In this study, we used zebrafish and single-cell RNA sequencing to understand how loss of RARS2 affects early brain development. We found that RARS2 deficiency damages mitochondrial structure, disrupts normal neuronal development, and promotes abnormal glial and stress-related programs. Our findings connect mitochondrial translation defects with altered gene regulation, RNA-processing pathways, and disturbed neural cell fate. This work provides a clearer framework for understanding RARS2-related disease and may help guide future studies of mitochondrial neurodevelopmental disorders. (https://jmg.bmj.com/content/early/2026/07/29/jmg-2025-111413)

Wild-type and rars2−/− embryos with brightfield and fluorescence staining in the head region