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NOC4L, a critical factor in ribosome biogenesis, participates in the maturation of the 40S small ribosomal subunit. However, its functions in neural and cartilage development remain incompletely understood. In this study, through generation and phenotypic characterization of a zebrafish noc4l knockout model, we identified severe developmental abnormalities including microcephaly, micrognathia, and embryonic lethality. Further analyses revealed that noc4l loss-of-function results in reduced proliferation, differentiation blockade, and apoptotic activation. Mechanistically, sucrose gradient analysis demonstrated the disrupted ribosome biogenesis in noc4l mutants, with significantly reduced 40S\/80S subunits and polysome levels, ultimately leading to overall translational inhibition and concurrent suppression of metabolic pathways. Pharmacological PPAR\u03b3 activation via rosiglitazone partially rescued craniofacial malformations, ameliorated neurodevelopmental defects, and prolonged mutant life span. Although inhibition of the p53 pathway can partially rescue the phenotype, the p53 pathway and metabolic pathways are likely independent contributing factors. Our study reveals the molecular basis of developmental defects in noc4l mutants through impaired ribosome assembly and demonstrates the therapeutic potential of metabolic interventions for ribosomopathies.<\/jats:p>","DOI":"10.1093\/jmcb\/mjaf052","type":"journal-article","created":{"date-parts":[[2025,12,6]],"date-time":"2025-12-06T12:58:11Z","timestamp":1765025891000},"source":"Crossref","is-referenced-by-count":0,"title":["NOC4L coordinates neuronal and pharyngeal arch development by regulating ribosome biogenesis"],"prefix":"10.1093","volume":"17","author":[{"given":"Tujing","family":"Song","sequence":"first","affiliation":[{"name":"Zhanjiang Key Laboratory of Zebrafish Model for Development and Disease, Affiliated Hospital of Guangdong Medical University , Zhanjiang 524001 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Liu","sequence":"additional","affiliation":[{"name":"School of Medical Technology, Guangdong Medical University , Dongguan 523808 ,","place":["China"]},{"name":"Zhanjiang Key Laboratory of Zebrafish Model for Development and Disease, Affiliated Hospital of Guangdong Medical University , Zhanjiang 524001 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunxiang","family":"Zhou","sequence":"additional","affiliation":[{"name":"Zhanjiang Key Laboratory of Zebrafish Model for Development and Disease, Affiliated Hospital of Guangdong Medical University , Zhanjiang 524001 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyu","family":"Li","sequence":"additional","affiliation":[{"name":"Zhanjiang Key Laboratory of Zebrafish Model for Development and Disease, Affiliated Hospital of Guangdong Medical University , Zhanjiang 524001 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liang","family":"Zhang","sequence":"additional","affiliation":[{"name":"Research Center of Translational Medicine, Jinan Central Hospital Affiliated to Shandong First Medical University , Jinan 250013 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guozhu","family":"Ning","sequence":"additional","affiliation":[{"name":"Zhanjiang Key Laboratory of Zebrafish Model for Development and Disease, Affiliated Hospital of Guangdong Medical University , Zhanjiang 524001 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Zhanjiang Key Laboratory of Zebrafish Model for Development and Disease, Affiliated Hospital of Guangdong Medical University , Zhanjiang 524001 ,","place":["China"]},{"name":"School of Medical Technology, Guangdong Medical University , Dongguan 523808 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,12,8]]},"reference":[{"key":"2026070205414929900_bib1","doi-asserted-by":"crossref","first-page":"1711","DOI":"10.1016\/S0002-9440(10)62481-9","article-title":"Sustained osteomalacia of long bones despite major improvement in other hypophosphatasia-related mineral deficits in tissue nonspecific alkaline phosphatase\/nucleotide pyrophosphatase phosphodiesterase 1 double-deficient mice","volume":"166","author":"Anderson","year":"2005","journal-title":"Am. 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