Sohet et al. demonstrate that the tricellular tight junction protein LSR helps form the blood–brain barrier during embryogenesis.
The blood–brain barrier protects neurons from the contents of the circulatory system and relies, in part, on the formation of tight junctions between the endothelial cells lining the blood vessels of the central nervous system. Mice lacking the tight junction protein claudin 5, for example, develop a leaky blood–brain barrier and die shortly after birth. But, because claudin 5 is expressed in all endothelial cells, it remains unclear why blood vessels in the brain are so much more impermeable than the blood vessels supplying other tissues.
Sohet et al. were interested in a protein called LSR that, in epithelial tissues, localizes to tight junctions at the points where three neighboring cells contact one another. LSR was also enriched at the tricellular tight junctions of central nervous system endothelial cells, the researchers found, but wasn’t expressed in the blood vessels of other mouse tissues. LSR was expressed in brain endothelial cells at the time—embryonic day E14.5—that the blood–brain barrier became impermeable to small molecules. In mice lacking LSR, however, the barrier failed to seal before the animals died at E15.5.
The blood–brain barrier is often disrupted by neurological injury or disease. Sohet et al. found that LSR was down-regulated in the leaky brain blood vessels generated in mouse models of both multiple sclerosis and stroke. The authors now want to investigate how this down-regulation occurs and whether preventing it can help maintain the blood–brain barrier’s integrity.
Text by Ben Short