期刊
PLOS GENETICS
卷 8, 期 8, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1002937
关键词
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资金
- NIDCR Intramural Research Program
- Augustinus Foundation
- Kobmand Kristian Kjaer og Hustrus Foundation
- Kjaer-Foundation
- Dagmar Marshalls Foundation
- Snedkermester Sophus Jacobsen og Hustru Astrid Jacobsens Foundation
- Grosserer Valdemar Foersom og Hustru Thyra Foersoms Foundation
- Fabrikant Einar Willumsens Mindelegat
- Harboe Foundation
- Lundbeck Foundation
- Swiss National Science Foundation [31003A-127147/1]
- INSERM Avenir
- Marie Curie Actions
- French National Research Agency
- Ile-de-France Region
- Swiss National Science Foundation (SNF) [31003A_127147] Funding Source: Swiss National Science Foundation (SNF)
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.
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