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