The fidelity of mRNA translation as a novel regulatory layer for brain development

Although the fidelity of mRNA translation is essential for maintaining proteome integrity, whether translation error rates vary across cell types and developmental stages in vivo remains largely unexplored. Here, we generate a gain-of-activity dual-luciferase knock-in reporter mouse that enables quantitative monitoring of translation errors in vivo. Using this system, we systematically characterize the spatiotemporal dynamics of translation fidelity across mammalian development. Mature organs exhibit lower error rates than pluripotent embryonic stem cells. Translation fidelity diverges sharply among organs, becoming progressively established during embryonic development, with brain and muscle displaying the highest accuracy. To determine functional significance, we experimentally increased translation errors during cerebral organoid formation and in vitro neuronal differentiation. Elevated error rates reduced neuronal output by impairing neuronal maturation without altering neural progenitor populations. Consistently, differentiated neurons display uniformly elevated fidelity across multiple classes of translation errors, including stop codon readthrough, amino acid misincorporation, and ribosomal frameshifting. These findings demonstrate that translation fidelity is not a fixed intrinsic property of the translation machinery but is developmentally regulated and required for efficient neuronal differentiation. Together, our results identify translation fidelity as a developmentally tuned, tissue-specific dimension of gene expression in vivo.