In a collaborative study, scientists from the University of Bern and the German Mouse Clinic investigated the impact of the claudin family member 12 on the blood-brain barrier function and found out, that it has different roles than forming tight junctions in the cells. The results were recently published in “Fluids and Barriers in the CNS”.
The blood–brain barrier (BBB) ensures central nervous system (CNS) homeostasis by strictly controlling the passage of molecules and solutes from the bloodstream into the CNS. Tight junctions (TJs) between brain endothelial cells block uncontrolled paracellular diffusion of molecules across the BBB. Claudin-5 is the dominant TJs protein, but studies suggest the contribution of other claudins in establishing BBB junctional complexes. The expression of claudin-12 at the BBB has been reported, but the exact function and subcellular localization of this atypical claudin remains unknown.
To analyze the expression of claudin-12 and to explore the role in establishing BBB TJs function during health and neuroinflammation, the researchers generated claudin-12-lacZ-knock-in mice, replacing the claudin-12 gene by the lacZ reporter gene. Claudin-12 seemed to be broadly expressed in numerous organs; also in the CNS expression was detected in many cell types. Claudin-12 deficient mice displayed an intact BBB and did not show any signs of BBB dysfunction or aggravated neuroinflammation in an animal model for multiple sclerosis.
To clarify, if the lack of claudin-12 in the CNS leads to neurological alterations independent from BBB maintenance, or if claudin-12 deficiency in other organs would affect entirely different physiological functions, the German Mouse Clinic performed an in depth phenotypic screening of the mouse model. Claudin-12 deficient mice displayed a number of mostly subtle phenotypic changes in several organ systems that correlate to the ubiquitous expression of claudin-12. Of note, the analysis of basic behavioral and motor functions in the Open Field assay showed decreased locomotor activity in claudin-KI mice and decreased anxiety in female mutant mice, suggesting the involvement of claudin-12 in neurological functions. In addition, the heart functionality seemed to be affected. The next step would be to unravel the role of this special claudin in cells and in cellular structures, especially in the CNS and in heart.
M Castro Dias, C Coisne, P Baden, G Enzmann, L Garrett, L Becker, S M. Hölter, German Mouse Clinic Consortium, M Hrabě de Angelis, U Deutsch and B Engelhardt: Claudin-12 is not required for blood-brain barrier tight junction function. Fluids barriers CNS 16:30 (2019)