Numerous membrane-associated proteases (for example, matriptase) modulate cell behaviour during development. Consequently, mutations in the inhibitors that control the activity of these proteases can have dire developmental effects. For example, mutations in the human SPINT2 gene, which encodes the serine protease inhibitor HAI2, cause organogenesis defects. Now,Szabo and colleagues report that HAI2 is essential for placental development,neural tube closure and embryonic survival in mice (see p. 2653). The researchers identify matriptase as a key target for HAI2 during mouse tissue morphogenesis and show that the inactivation of matriptase in HAI2-deficient embryos completely restores placental development and embryonic survival; the incomplete prevention of neural tube defects in these doubly deficient embryos suggests, however, that HAI2 has additional targets during neural development. Finally, the researchers use genetic complementation to reveal that a functional interaction between HAI2 and the related inhibitor HAI1 regulates matriptase activity during development. Thus, they suggest, tissue morphogenesis requires the regulation of membrane-associated serine proteases by a network of partly redundant inhibitors.

2009