title: Matriptase inhibition by hepatocyte growth factor activator inhibitor-1 is essential for placental development.
abstract: Hepatocyte growth factor activator inhibitor-1 (HAI-1) is a Kunitz-type transmembrane serine protease inhibitor that forms inhibitor complexes with several trypsin-like serine proteases and is required for mouse placental development and embryo survival. Here we show that the essential function of HAI-1 in placentation and all other embryonic processes is to restrict the activity of the type II transmembrane serine protease, matriptase. Enzymatic gene trapping of matriptase combined with HAI-1 immunohistochemistry revealed that matriptase is co-expressed with HAI-1 in both extraembryonic and embryonic tissues. As early as embryonic day 8.5, matriptase and HAI-1 were expressed in a population of chorionic trophoblasts. Ablation of HAI-1 disrupted the epithelial integrity of this cell population, causing disorganized laminin deposition and altered expression of E-cadherin and beta-catenin. This led to a complete loss of undifferentiated chorionic trophoblasts after embryonic day 9.5 and prevented the formation of the placental labyrinth. Genetic ablation of matriptase activity in HAI-1-deficient embryos, however, restored the integrity of chorionic trophoblasts and enabled placental labyrinth formation and development to term. Furthermore, matriptase/HAI-1 double-deficient mice were phenotypically indistinguishable from matriptase single-deficient littermates.
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: R
authors.initials: R
authors.lastname: Szabo
authors.forename: A
authors.initials: A
authors.lastname: Molinolo
authors.forename: K
authors.initials: K
authors.lastname: List
authors.forename: T H
authors.initials: TH
authors.lastname: Bugge
mesh_terms: D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D010929:Placentation; D053491:Proteinase Inhibitory Proteins, Secretory; D012697:Serine Endopeptidases / Q000187:drug effects*
chemical_list: D017931:DNA Primers; D008562:Membrane Glycoproteins; D053491:Proteinase Inhibitory Proteins, Secretory; C109149:SPINT1 protein, human; C504591:Spint1 protein, mouse; D012697:Serine Endopeptidases; C485595:matriptase