A cross-species transcriptomic comparison to identify novel genetic regulators of BBB maintenance

The blood-brain barrier (BBB) is a dynamic interface between the central nervous system (CNS) and peripheral blood circulation that ensures CNS homeostasis and is formed at the brain endothelial cells (BECs) lining the walls of brain capillaries by interactions between components of the neurovascular unit. In recent years, increasing evidence implicating its role in neurological disorders has led to enhanced efforts to improve our understanding of molecular mechanisms involved in maintaining BBB function. To this end, recent approaches using transcriptomic analyses have identified novel BBB regulators such as DR6 (Tnfrsf21)/TROY (Tnfrsf19), vitronectin (Vtn), Mfsd2a and PAR bZIP transcription factors, albeit inefficiently, relying on making educated guesstimates from large transcriptomic datasets. To meaningfully select candidate genes, we leveraged the conserved role of BBB function across vertebrates, from teleost fish such as zebrafish to mammals such as mice and humans. This comparison provided us with a list of evolutionarily-conserved-BBB-enriched transcripts termed the “core BBB transcriptome.” The presence of previously reported BBB genes such as Cldn5, Slc2a1, Foxf2 validate the core BBB transcriptome. The core BBB transcriptome serves as a guide for further selection of candidate genes to be assessed for their role in maintaining BBB function by reverse genetic approaches in zebrafish and mice.