Regionally defined proteomic profiles of human cerebral tissue and organoids reveal conserved molecular modules of neurodevelopment

Cerebral organoids have emerged as faithful humanoid avatars for modeling neurodevelopmental and pathological processes. Additionally, they serve as powerful discovery platforms for less characterized neurobiological programs. Towards this prospect, we leveraged mass spectrometry-based proteomics to molecularly profile precursor and neural compartments of both human-derived organoids and mid-gestation fetal brain tissue, to define overlapping programs. Our analysis included precursor-enriched transcriptional regulatory proteins that were not found to be differentially expressed in previous transcriptomic datasets. To highlight the discovery potential of this resource, we show that RUVBL2 is preferentially expressed in the SOX2-positive compartment of organoids and chemical inactivation leads to precursor cell displacement and apoptosis. To explore clinicopathological correlates of this cytoarchitectural disruption, we interrogated clinical datasets, and identified rare de novo genetic variants involving RUVBL2 in patients with neurodevelopmental impairments. Together, our study demonstrates how cell-type specific profiling of organoids can help nominate previously unappreciated genes in neurodevelopment and disease.