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A programmed decline in ribosome levels governs human early neurodevelopment
Chunyang Ni1, Yudong Wei1, Barbara Vona2,3
1Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Nature Cell Biology
|August 5, 2025
Summary
Variants in AIRIM/C1orf109 cause neurodevelopmental disorders by disrupting protein production during brain development. Reduced ribosome biogenesis impacts cell survival and fate, highlighting the importance of protein synthesis regulation.
Area of Science:
- Genetics
- Developmental Biology
- Neuroscience
Background:
- Neurodevelopmental defects are often linked to genes involved in essential cellular functions like ribosome biogenesis.
- The precise mechanisms by which reduced ribosome biogenesis leads to specific developmental issues are not fully understood.
Purpose of the Study:
- To investigate the role of the ribosome biogenesis factor AIRIM/C1orf109 in neurodevelopmental disorders.
- To elucidate how perturbations in ribosome biogenesis affect early brain development and cellular processes.
Main Methods:
- Utilized human cerebral organoids for studying neurodevelopment.
- Employed proteomic, single-cell RNA sequencing, and single-organoid translation analyses.
- Investigated the impact of AIRIM/C1orf109 variants on protein synthesis and cellular functions.
Main Results:
- Identified variants in AIRIM/C1orf109 associated with neurodevelopmental disorders.
- Discovered a significant decrease in protein production during early brain development, particularly during neuroepithelial differentiation.
- Found that reduced ribosome availability disproportionately affects specific transcripts, impacting cell survival and fate commitment.
- Demonstrated that enhancing mTOR activity can rescue the observed growth and developmental defects.
Conclusions:
- Regulated changes in protein synthesis capacity are crucial during cellular differentiation in the brain.
- AIRIM/C1orf109 plays a critical role in maintaining protein synthesis during neurodevelopment.
- Perturbations in ribosome biogenesis during critical developmental windows can lead to neurodevelopmental disorders.
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