Spatiotemporal 22q11.21 Protein Network Implicates DGCR8-Dependent MicroRNA Biogenesis as a Risk for Late Fetal Cortical Development in Psychiatric Diseases

Abstract

The chromosome 22q11.21 copy number variant (CNV) is a vital risk factor that can be a genetic predisposition to neurodevelopmental disorders (NDD). As the 22q11.21 CNV affects multiple genes, causal disease genes and mechanisms affected are still poorly understood. Thus, we aimed to identify the most impactful 22q11.21 CNV genes and the potential impacted human brain regions, developmental stages and signaling pathways. We constructed the spatiotemporal dynamic networks of 22q11.21 CNV genes using the brain developmental transcriptome and physical protein–protein interactions. The affected brain regions, developmental stages, driver genes and pathways were subsequently investigated via integrated bioinformatics analysis. As a result, we first identified that 22q11.21 CNV genes affect the cortical area mainly during late fetal periods. Interestingly, we observed that connections between a driver gene, DGCR8, and its interacting partners, MECP2 and CUL3, also network hubs, only existed in the network of the late fetal period within the cortical region, suggesting their functional specificity during brain development. We also confirmed the physical interaction result between DGCR8 and CUL3 by liquid chromatography-tandem mass spectrometry. In conclusion, our results could suggest that the disruption of DGCR8-dependent microRNA biogenesis plays a vital role in NDD for late fetal cortical development.