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Matriptase inhibition by hepatocyte growth factor activator inhibitor-1 is essential for placental development

Oncogene volume 26, pages 1546–1556 (2007)Cite this article

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 β-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.

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Abbreviations

E:

embryonic day

ES:

embryonic stem (cells)

HAI:

hepatocyte growth factor activator inhibitor

X-gal:

5-bromo-4-chloro-3-indolyl-beta-D-galactopyranoside

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Acknowledgements

We thank Drs Chen-Yong Lin and Robert Dickson for generously providing human matriptase antibody, and Drs Silvio Gutkind and Mary Jo Danton for critically reviewing this manuscript. This work was supported by the NIH Intramural program and by a grant from the Department of Defense (DAMD-17-02-1-0693) to Dr Thomas H Bugge.

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Authors and Affiliations

  1. Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA

    R Szabo, A Molinolo, K List & T H Bugge

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  1. R Szabo
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  2. A Molinolo
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  3. K List
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  4. T H Bugge
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Correspondence to T H Bugge.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Szabo, R., Molinolo, A., List, K. et al. Matriptase inhibition by hepatocyte growth factor activator inhibitor-1 is essential for placental development. Oncogene 26, 1546–1556 (2007). https://doi.org/10.1038/sj.onc.1209966

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