广东医科大学张晶晶小组取得一项新突破。他们的最新研究探明了NOC4L通过调节核糖体的生物发生来协调神经元和咽弓的发育。这一研究成果发表在2025年12月8日出版的国际学术期刊《分子细胞生物学报》上。

在这项研究中，通过斑马鱼NOC4L基因敲除模型的产生和表型表征，课题组发现了严重的发育异常，包括小头畸形、小颌畸形和胚胎致死。进一步分析显示，NOC4L功能缺失导致细胞增殖减少、分化阻断和凋亡激活。在机制上，蔗糖梯度分析表明，在NOC4L突变体中，核糖体的生物发生被破坏，40S/80S亚基和多聚体水平显著降低，最终导致整体的翻译抑制和代谢途径的同时抑制。罗格列酮激活PPARγ可部分挽救颅面畸形，改善神经发育缺陷，延长突变体寿命。虽然抑制p53途径可以部分挽救表型，但p53途径和代谢途径可能是独立的促成因素。他们的研究通过核糖体组装受损揭示了NOC4L突变体发育缺陷的分子基础，并证明了代谢干预对核糖体病的治疗潜力。

据了解，核糖体生物发生相关基因的突变或核糖体蛋白的功能缺陷可导致一类以组织特异性缺陷为特征的常染色体遗传疾病，称为核糖体病。NOC4L是核糖体生物发生的关键因子，参与40S小核糖体亚基的成熟。然而，其在神经和软骨发育中的功能仍不完全清楚。

附：英文原文

Title: NOC4L coordinates neuronal and pharyngeal arch development by regulating ribosome biogenesis

Author: Song, Tujing, Liu, Yan, Zhou, Yunxiang, Li, Xiaoyu, Zhang, Liang, Ning, Guozhu, Zhang, Jingjing

Issue&Volume: 2025-12-08

Abstract: Mutations in ribosome biogenesis-related genes or functional defects in ribosomal proteins can lead to a class of autosomal genetic disorders characterized by tissue-specific defects, termed ribosomopathies. 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 PPARγ 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.

DOI: 10.1093/jmcb/mjaf052

Source: https://dx.doi.org/10.1093/jmcb/mjaf052