Reduced Prostasin (CAP1/PRSS8) Activity Eliminates HAI-1 and HAI-2 Deficiency-Associated Developmental Defects by Preventing Matriptase Activation

Loss of either hepatocyte growth factor activator inhibitor (hai)-1 or -2 is associated with embryonic lethality in mice,which can be rescued by the simultaneous inactivation of the membrane-anchored serine protease,matriptase,thereby demonstrating that a matriptase-dependent proteolytic pathway is a critical developmental target for both protease inhibitors. here,we performed a genetic epistasis analysis to identify additional components of this pathway by generating mice with combined deficiency in either hai-1 or hai-2,along with genes encoding developmentally co-expressed candidate matriptase targets,and screening for the rescue of embryonic development. hypomorphic mutations in prss8,encoding the gpi-anchored serine protease,prostasin (cap1,prss8),restored placentation and normal development of hai-1-deficient embryos and prevented early embryonic lethality,mid-gestation lethality due to placental labyrinth failure,and neural tube defects in hai-2-deficient embryos. inactivation of genes encoding c-met,protease-activated receptor-2 (par-2),or the epithelial sodium channel (enac) alpha subunit all failed to rescue embryonic lethality,suggesting that deregulated matriptase-prostasin activity causes developmental failure independent of aberrant c-met and par-2 signaling or impaired epithelial sodium transport. furthermore,phenotypic analysis of par-1 and matriptase double-deficient embryos suggests that the protease may not be critical for focal proteolytic activation of par-2 during neural tube closure. paradoxically,although matriptase auto-activates and is a well-established upstream epidermal activator of prostasin,biochemical analysis of matriptase- and prostasin-deficient placental tissues revealed a requirement of prostasin for conversion of the matriptase zymogen to active matriptase,whereas prostasin zymogen activation was matriptase-independent. © 2012.