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A comparative analysis of zebrafish and mouse blood-brain barrier transcriptomes identifies novel regulators of neurovascular development

par Panji, Jay
Président du jury Vanhamme, Luc
Promoteur Vanhollebeke, Benoît
Publication Non publié, 2026-10-14

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Résumé :

The endothelial blood-brain barrier (BBB) is a multifaceted neuroprotective structure. BBB dysfunction has been implicated in neurological disorders, thereby prompting research into mechanisms regulating BBB function. To this end, transcriptomic characterizations have been utilized to identify novel BBB regulators. However, the discovery rate of novel BBB modulators has remained slow. This is chiefly because candidate genes are selected based on transcript levels or inferred functions from transcriptomic datasets and functionally evaluated in vivo using time-consuming Mendelian genetics approaches. Studies in zebrafish and mice have shown that BBB function is largely conserved across vertebrate evolution, suggesting that the BBB may have evolved from a common ancestor. If so, investigating the shared BBB-enriched transcripts between both species would facilitate faster identification of novel BBB regulators. To this end, we performed a comparative analysis of the zebrafish and mouse BBB transcriptomes, for which we first characterized the zebrafish BBB transcriptome. In this regard, we developed novel BBB labeling techniques and identified transcripts enriched in BBB endothelial cells (ECs) compared to peripheral ECs. Upon comparison with published mouse BBB transcriptomes, we uncovered shared BBB-enriched transcripts indicating early evolution of BBB immune quiescence in vertebrates and similarities in BBB regulation. We also uncovered species-specific features corresponding to habitat-enforced adaptations and differences in the modulation of BBB permeability. To investigate the shared BBB-enriched transcripts at a faster rate, we leveraged the complementary anatomical advantages of both model organisms along with gene disruption using CRISPR/Cas9 for parallel investigation of candidate gene function in brain angiogenesis and BBB integrity. Using the developed tools, we screened a subset of shared BBB-enriched transcripts and identified novel transcription factors regulating brain angiogenesis. Taken together, this work uncovered the shared transcriptional regulation of neurovascular development in vertebrates.