Transcriptomic Analyses of Brains of RBM8A Conditional Knockout Mice at Different Developmental Stages Reveal Conserved Signaling Pathways Contributing to Neurodevelopmental Diseases

RNA-binding motif 8A (RBM8A) is a core component of the exon junction complex (EJC) that binds pre-mRNAs and regulates their splicing, transport, translation, and nonsense-mediated decay (NMD). Dysfunction in the core proteins has been linked to several detriments in brain development and neuropsychiatric diseases. To understand the functional role of Rbm8a in brain development, we have generated brain-specific Rbm8a knockout mice and used next-generation RNA-sequencing to identify differentially expressed genes (DEGs) in mice with heterozygous, conditional knockout (cKO) of Rbm8a in the brain at postnatal day 17 (P17) and at embryonic day 12. Additionally, we analyzed enriched gene clusters and signaling pathways within the DEGs. At the P17 time point, between the control and cKO mice, about 251 significant DEGs were identified. At E12, only 25 DEGs were identified in the hindbrain samples. Bioinformatics analyses have revealed many signaling pathways related to the central nervous system (CNS). When E12 and P17 results were compared, three DEGs, Spp1, Gpnmb, and Top2a, appeared to peak at different developmental time points in the Rbm8a cKO mice. Enrichment analyses suggested altered activity in pathways affecting cellular proliferation, differentiation, and survival. The results support the hypothesis that loss of Rbm8a causes decreased cellular proliferation, increased apoptosis, and early differentiation of neuronal subtypes, which may lead ultimately to an altered neuronal subtype composition in the brain.

Automated summary

RNA-binding motif 8A (RBM8A) is a core component of the exon junction complex (EJC) that regulates various processes in mRNA, including splicing and translation. The researchers generated brain-specific Rbm8a knockout mice to investigate its role in brain development. They found that loss of Rbm8a resulted in altered gene expression and disrupted signaling pathways related to the central nervous system. The study suggests that Rbm8a is important for cellular proliferation, apoptosis, and neuronal subtype differentiation in the brain.