biostudies-literatureNi CDeutsche Stiftung Friedensforschung (German Foundation for Peace Research)Chinese Academy of Sciences (CAS)U.S. Department of Health & Human Services | NIH | National Institute of General Medical SciencesNICHD NIH HHSU.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences (NIGMS)NIA NIH HHSCancer Prevention and Research Institute of TexasU.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human DevelopmentU.S. Department of Health & Human Services | NIH | National Cancer InstituteRCUK | Biotechnology and Biological Sciences Research CouncilNINDS NIH HHSWelch FoundationBiotechnology and Biological Sciences Research CouncilU.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)Chinese Academy of SciencesCancer Prevention and Research Institute of Texas (Cancer Prevention Research Institute of Texas)U.S. Department of Health & Human Services | NIH | National Institute on AgingU.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and StrokeDeutsche Stiftung FriedensforschungU.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)Wellcome TrustNIGMS NIH HHSPenn | Perelman School of Medicine at the University of Pennsylvania | Abramson Family Cancer Research Institute1240-1255https://www.ebi.ac.uk/biostudies/studies/S-EPMC12339376biostudies-literatureUnknown27(8)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 tNature cell biologyA programmed decline in ribosome levels governs human early neurodevelopment.PMC12339376I-2088R01AG067604R01 GM101149222531/Z/21/ZGM101149NS125906BB/Z51522X/1R01 HD103627R35GM144043RR180042CA174905R01AG079513R01 AG079513R35 GM144043R01 GM138565F-2027-20230405HD103627F31 NS125906R01 AG067604GM138565XDB0820000DFG VO 2138/7-1Wu JBuszczak MXing CBadv RSJeong WCEghbal FMaroofian RRamzan KBallard EMetanat ZEslamiyeh HNi CZeqiraj EAlluqmani MMGreenberg RADehghani MHoulden HKarimiani EGMarinakis NMCenik CLi LMehrjardi MYVSchwaibold EMCKhouj ESakurai MPark DYu LUmair MSofocleous CLee HVorgia PSchmitz DAWei YQin SLiu YDing YEkmekci CAlhajj SMNBilal MImannezhad SZhao JAlves CAPFChedrawi AKim HGHashmi JAKim SSieber MAlkuraya FSKruer MBasit SVeltra DFoglizzo MNiotakis GKumar AVona BfalseA programmed decline in ribosome levels governs human early neurodevelopment.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 t2025-01-01T00:00:00Z2025 Aug2026-07-15T08:58:20.96Z2026-07-03T03:10:30.74ZS-EPMC123393764076024710.1038/s41556-025-01708-8