Combined loss of matriptase/prostasin- and PAR-2-dependent proteolytic pathways leads to embryonic lethality.

<p>(<b>A</b>). Matriptase haploinsufficiency decreases survival of PAR-2-deficient mice. Genotype distribution among 706 pre-weaning offspring from interbred <i>F2rl1^+/−</i>×<i>F2rl1</i>^+/−<i>;St14^+/−</i> mice. A normal distribution of <i>F2rl1</i> alleles was observed in <i>St14^+/+</i> background, whereas the number of <i>F2rl1^−/−</i> mice heterozygous for matriptase was significantly decreased (P<0.0001). (<b>B</b>). Genotype distribution among 272 newborn offspring from interbred <i>F2rl1^+/−;St14^+/−</i>×<i>F2rl1</i>^+/−;<i>St14^+/−</i> mice. <i>F2rl1</i> alleles were found in the expected Mendelian ratio in <i>St14^+/+</i> mice, whereas numbers of <i>F2rl1^−/−;St14^+/−</i> and <i>F2rl1^+/−;St14^−/−</i> mice was significantly reduced, and no <i>F2rl1^−/−;St14^−/−</i> mice were observed (P<0.0001). (<b>C</b>). Relative prenatal survival of PAR-2-deficient (<i>F2rl1^−/−</i>, blue bars) and matriptase-deficient (<i>St14^−/−</i>, green bars) mice shown in (<b>B</b>) as a function of gene dosage of <i>St14</i> and <i>F2rl1</i> genes, respectively. Survival of PAR-2-deficient animals decreased from 90% in <i>St14^+/+</i> background, to 40% in <i>St14^+/−</i> and 0% in <i>St14^−/−</i> background. Similarly, survival of matriptase-deficient mice decreased from 73% in <i>F2rl1^+/+</i> animals to 35% in <i>F2rl1^+/−</i> and 0% in the PAR-2-deficient <i>F2rl1^−/−</i> animals. (<b>D</b>). Genotype distribution among 247 newborn offspring from interbred <i>F2rl1^+/−;Prss8^+/−</i>×<i>F2rl1</i>^+/−;<i>Prss8^+/−</i> mice. <i>F2rl1</i> alleles were found in the expected Mendelian ratio in <i>Prss8^+/+</i> mice, whereas numbers of <i>F2rl1^−/−;Prss8^+/−</i> and <i>F2rl1^+/−;Prss8^−/−</i> mice was significantly reduced, and no <i>F2rl1^−/−;Prss8^−/−</i> mice were observed (P<0.0005). (<b>E, F</b>). Survival of <i>F2rl1^−/−;St14^−/−</i> (<b>E</b>) and <i>F2rl1^−/−;Prss8^−/−</i> (<b>F</b>) embryos before birth, relative to the expected Mendelian distribution. (<b>E</b>). PAR-2/matriptase double-deficient embryos were detected in expected numbers at or before E12.5, followed by a decrease to 59% at E13.5 (N = 251), and 15% at E14.5 (N = 90). No surviving <i>F2rl1^−/−;St14^−/−</i> animals were detected at or after E15.5. (<b>F</b>). PAR-2 and prostasin double-deficient embryos were detected in expected numbers at E11.5, followed by a gradual decrease to 80% at E12.5 (N = 90), 47% at E13.5 (N = 176), and 17% at E14.5 (N = 68). No surviving <i>F2rl1^−/−;Prss8^−/−</i> animals were detected at or after E15.5.