Abstract
ABSTRACTThe central nervous system (CNS) has specific barriers that protect the brain from potential threats and tightly regulate molecular transport. Despite the critical functions of the CNS barriers, the mechanisms underlying their development and function are not well understood, and there are very limited experimental models for their study. Claudin 5 is a tight junction protein required for blood brain barrier (BBB) and, probably, choroid plexus (CP) structure and function in vertebrates. Here, we show that the gene claudin 5a is the zebrafish orthologue with high fidelity expression, in the BBB and CP barriers, that demonstrates the conservation of the BBB and CP between humans and zebrafish. Expression of claudin 5a correlates with developmental tightening of the BBB and is restricted to a subset of the brain vasculature clearly delineating the BBB. We show that claudin 5a-expressing cells of the CP are ciliated ependymal cells that drive fluid flow in the brain ventricles. Finally, we find that CP development precedes BBB development and that claudin 5a expression occurs simultaneously with angiogenesis. Thus, our novel transgenic zebrafish represents an ideal model to study CNS barrier development and function, critical in understanding the mechanisms underlying CNS barrier function in health and disease.
Highlights
The central nervous system (CNS) is protected by three specialized barriers that shield the vulnerable brain tissue from potential threats and actively regulate exchange of ions and nutrients
Examination of zebrafish expression patterns (Thisse et al, 2004) showed that claudin 5a was expressed in the CNS ventricle region while claudin 5b had a cardiovascular patterning
Claudin 5 as a prominent tight junctions (TJs) protein is a consistent feature between the blood brain barrier (BBB) and blood-cerebrospinal fluid (CSF) barrier (Bill and Korzh, 2014)
Summary
The central nervous system (CNS) is protected by three specialized barriers that shield the vulnerable brain tissue from potential threats and actively regulate exchange of ions and nutrients. The blood brain barrier (BBB) is formed by endothelial cells between blood and brain interstitial fluid and has extensive control over the immediate microenvironment of the CNS (Abbott et al, 2006, 2010). Less studied are the blood-cerebrospinal fluid (CSF) barrier, A.M.v.d.S., 0000-0001-5790-5036. The BBB and blood-CSF barrier tissues have tight junctions (TJs), consisting of protein complexes that seal adjacent cells and actively regulate barrier integrity (Greene and Campbell, 2016). Claudin 5 is the most strongly expressed in mammalian brain microvessels (Zhang et al, 2012) This protein was shown to be important for barrier integrity in mice, the expression of claudin 5 is not conserved in the murine CP and is not a definitive marker of the BBB (Nitta et al, 2003)
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