NOC4L coordinates neuronal and pharyngeal arch development by regulating ribosome biogenesis-related processes

Bowen-Conradi syndrome (BCS) is an autosomal-recessive disease marked by lethality and characterized by neurodevelopmental delays, microcephaly, and craniofacial abnormalities, yet remains mechanistically underexplored due to the absence of robust biological models. To address this gap, we generated the first vertebrate model of BCS through CRISPR-Cas9-mediated noc4l knockout in zebrafish. Our model recapitulates key clinical features observed in BCS patients, including microcephaly, micrognathia, and developmental delay. Histopathology revealed diminished cell proliferation and elevated apoptosis within cephalic and pharyngeal arch regions of mutants. Molecular characterization revealed that rRNA processing defects impaired ribosome biogenesis, reducing 40S and 80S subunits and polysomes, ultimately leading to suppression of protein synthesis. Mechanistically, translatomic profiling identified PPAR? signaling as a significantly downregulated pathway in noc4l mutants. Rosiglitazone-induced PPAR? activation partially rescued cranial and pharyngeal cartilage defects, while also alleviating neurodevelopmental deficits. This work establishes impaired translational machinery as the pathogenic core of BCS and highlights PPAR? agonism as a viable therapeutic strategy, with rosiglitazone demonstrating preclinical efficacy in rescuing disease-relevant phenotypes. Our findings provide both a pathophysiological framework for BCS and a platform for testing translation-targeted interventions. Overall design: We cut the head of the siblings and the noc4l -/- mutants with 1-ml syringe needle. Total RNA of the head from embryos at 5 dpf were isolated using TRIzol. RNA-Seq and Ribo-seq were performed in the Gene Denovo Biotechnology (Guangzhou, China). Differentially expressed genes (DEGs) were detected using DESeq2. Reactome enrichment analysis and GO enrichment analysis were performed to elucidate the functional implications of DEGs. DEGs with a false discovery rate (FDR) of less than 0.05 were selected for enrichment analysis.