美国德克萨斯大学Michael Buszczak课题组近日取得一项新成果。经过不懈努力，他们提出了核糖体水平的程序性下降控制着人类早期神经发育。相关论文发表在2025年8月4日出版的《自然—细胞生物学》杂志上。

在这里，该研究团队描述了主要与神经发育障碍相关的核糖体生物发生因子AIRIM/C1orf109的变异。利用人类大脑类器官与蛋白质组学、单细胞RNA测序和单类器官翻译分析相结合，小组发现了在早期大脑发育过程中蛋白质产生的一个以前未被发现的下降。该课题组发现核糖体水平在神经上皮分化过程中下降，使分化细胞在此期间特别容易受到核糖体生物发生的干扰。核糖体可用性的降低更深刻地影响特定转录物的翻译，破坏移行神经上皮的存活和细胞命运承诺。增强mTOR活性可抑制与AIRIM/C1orf109变异相关的生长和发育缺陷。这项工作为细胞分化过程中全球蛋白质合成能力的调节变化的功能重要性提供了证据。

据介绍，许多神经发育缺陷与参与体温保持功能的基因有关，例如编码核糖体生物发生因子的基因。核糖体生物发生的减少如何导致组织和发育特异性缺陷仍不清楚。

附：英文原文

Title: A programmed decline in ribosome levels governs human early neurodevelopment

Author: Ni, Chunyang, Wei, Yudong, Vona, Barbara, Park, Dayea, Wei, Yulei, Schmitz, Daniel A., Ding, Yi, Sakurai, Masahiro, Ballard, Emily, Li, Leijie, Liu, Yan, Kumar, Ashwani, Xing, Chao, Qin, Shenlu, Kim, Sangin, Foglizzo, Martina, Zhao, Jianchao, Kim, Hyung-Goo, Ekmekci, Cumhur, Karimiani, Ehsan Ghayoor, Imannezhad, Shima, Eghbal, Fatemeh, Badv, Reza Shervin, Schwaibold, Eva Maria Christina, Dehghani, Mohammadreza, Mehrjardi, Mohammad Yahya Vahidi, Metanat, Zahra, Eslamiyeh, Hosein, Khouj, Ebtissal, Alhajj, Saleh Mohammed Nasser, Chedrawi, Aziza, Ramzan, Khushnooda, Hashmi, Jamil A., Alluqmani, Majed M., Basit, Sulman, Veltra, Danai, Marinakis, Nikolaos M., Niotakis, Georgios, Vorgia, Pelagia, Sofocleous, Christalena, Lee, Hane, Jeong, Won Chan, Umair, Muhammad, Bilal, Muhammad, Alves, Csar Augusto Pinheiro Ferreira, Sieber, Matthew, Kruer, Michael, Houlden, Henry, Alkuraya, Fowzan S., Zeqiraj, Elton, Greenberg, Roger A., Cenik, Can, Yu, Leqian, Maroofian, Reza, Wu, Jun, Buszczak, Michael

Issue&Volume: 2025-08-04

Abstract: Many neurodevelopmental defects are linked to genes involved in housekeeping functions, such as those encoding ribosome biogenesis factors. How reductions in ribosome biogenesis can result in tissue- and developmental-specific defects remains unclear. Here we describe variants in the ribosome biogenesis factor AIRIM/C1orf109 that are primarily associated with neurodevelopmental disorders. Using human cerebral organoids in combination with proteomic, single-cell RNA sequencing and single-organoid translation analyses, we identify a previously unappreciated drop in protein production during early brain development. We find that ribosome levels decrease during neuroepithelial differentiation, making differentiating cells particularly vulnerable to perturbations in ribosome biogenesis during this time. Reduced ribosome availability more profoundly impacts the translation of specific transcripts, disrupting both survival and cell fate commitment of transitioning neuroepithelia. Enhancing mTOR activity suppresses the growth and developmental defects associated with AIRIM/C1orf109 variants. This work provides evidence for the functional importance of regulated changes in global protein synthesis capacity during cellular differentiation.

DOI: 10.1038/s41556-025-01708-8

Source: https://www.nature.com/articles/s41556-025-01708-8