A programmed decline in ribosome levels governs human early neurodevelopment

How reductions in ribosome biogenesis can result in tissue- and developmental-specific defects remain a mystery. Here we describe allelic 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 transcriptome across multiple developmental stages, and single-organoid translatome analyses, we identify a previously unappreciated drop in protein production during early brain development. We find 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 by both genetic and pharmacologic methods suppresses the growth and developmental defects associated with intellectual disability linked variants. This work provides further evidence for the functional importance of regulated changes in global protein synthesis capacity during cellular differentiation.