Genome-wide analysis of genes encoding core components of the ubiquitin system during cerebral cortex development

Abstract Ubiquitination involves three types of enzymes (E1, E2, E3) acting sequentially to attach ubiquitin (Ub) to target proteins. This post-translational modification controls key cellular processes like the degradation of proteins, endocytosis, subcellular localization and activity of proteins. The ubiquitination, which can be reversed by deubiquitinating enzymes (DUBs), plays important roles during brain development. Furthermore, deregulation of the Ub system is linked to the pathogenesis of various diseases including neurodegenerative disorders. We have used a publicly available RNAseq database to conduct an extensive genome-wide gene expression analysis of the core components of the Ub machinery, covering Ub genes as well as E1, E2, E3 and DUB genes. The ubiquitination network was merely governed by Uba1 and Ube2m, the predominant E1 and E2 genes, respectively. There expression was positively regulated during cortical formation. The principal genes coding for HECT (homologous to the E6-AP carboxyl terminus), RBR (RING-in-between-RING), and RING (really interesting new gene) E3 Ub ligases were also prominently regulated. Pja1, Dtx3 (RING ligases) and Stub1 (U-box RING) were the most highly expressed E3 Ub ligase genes and displayed distinct developmental expression patterns. Moreover, > 80 DUB genes were expressed during corticogenesis with two prominent actors Uch-l1 and Usp22 that were strongly up-regulated. Several components of the Ub system overexpressed in cancers were highly expressed in the cerebral cortex under conditions not related to tumour formation or progression. Altogether, this work provides an in-depth overview of the transcriptomic changes during the embryonic formation of the cerebral cortex. The data also offer new insight for the characterization of the Ub system and may contribute to a better understanding of its involvement in the pathogenesis of neurodevelopmental disorders.