The blood–brain barrier (BBB), a selective physical and chemical barrier that insulates the nervous system from the body fluid, is crucial for maintaining a stable ionic environment and ensuring appropriate firing of neurons. Two studies, published in Cell, show that moody, a gene that encodes a newly identified G-protein-coupled receptor (GPCR), is necessary for the formation and maintenance of the fly BBB.

In a reverse genetic screen for factors with glial expression and function, Schwabe and colleagues identified two GPCRs, Moody and Tre1, as well as a regulator of G-protein signalling, Loco. Moody, Loco and the G-protein subunits Gαi and Gαo are expressed in the surface glia — the thin layer of epithelial cells that constitutes the fly BBB. Loco colocalizes with Moody at the plasma membrane, and physically interacts with Gαi and Gαo, which indicates that the four proteins are part of a common signalling pathway. When the expression of any of these factors is abolished in fly embryos using RNA interference, the BBB development is significantly compromised. In the case of moody, complete loss of function results in embryonic lethality due to defective insulation of the nervous system.

In the second study, Bainton and colleagues identified moody in a genetic screen for mutants with altered cocaine sensitivity. moody encodes two proteins, Moody-α and -β, which differ in their long carboxy-terminal domains. Both forms of Moody are expressed in the surface glia and at regions of cell–cell contact. When the expression of moody is transiently inhibited in adult flies, the BBB is disrupted in a reversible manner, which indicates that Moody is continuously required to insulate the nervous system. Interestingly, the role of Moody in drug sensitivity can be dissociated from its role in nervous system insulation, whereas either Moody-α or -β is sufficient for BBB formation, both protein forms are necessary for flies to show normal cocaine sensitivity.

As GPCRs and other newly identified molecules are important for the BBB in both flies and mammals, studies of the fly BBB could provide important insights into how the mammalian BBB is formed and regulated, and how this might lead to changes in drug sensitivities and other complex behaviours.