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Molecular and Cellular Biology, July 2005, p. 5687-5698, Vol. 25, No. 13
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.13.5687-5698.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Hepatocyte Growth Factor Activator Inhibitor Type 1 (HAI-1) Is Required for Branching Morphogenesis in the Chorioallantoic Placenta

Hiroyuki Tanaka,1 Koki Nagaike,1 Naoki Takeda,2 Hiroshi Itoh,1 Kazuyo Kohama,1 Tsuyoshi Fukushima,1 Shiro Miyata,1 Shuichiro Uchiyama,1 Shunro Uchinokura,1 Takeshi Shimomura,3 Keiji Miyazawa,4 Naomi Kitamura,5 Gen Yamada,2 and Hiroaki Kataoka1*

Second Department of Pathology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan,1 Center for Animal Resources and Development, Graduate School of Molecular and Genomic Pharmacy, Kumamoto University, Kumamoto, Japan,2 Yokohama Research Center, Mitsubishi Pharma Corporation, Yokohama, Japan,3 Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan,4 Department of Biological Sciences, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan5

Received 16 December 2004/ Returned for modification 3 February 2005/ Accepted 31 March 2005

Hepatocyte growth factor activator inhibitor type 1 (HAI-1) is a membrane-associated Kunitz-type serine proteinase inhibitor that was initially identified as a potent inhibitor of hepatocyte growth factor activator. HAI-1 is also a cognate inhibitor of matriptase, a membrane-associated serine proteinase. HAI-1 is expressed predominantly in epithelial cells in the human body. Its mRNA is also abundant in human placenta, with HAI-1 specifically expressed by villous cytotrophoblasts. In order to address the precise roles of HAI-1 in vivo, we generated HAI-1 mutant mice by homozygous recombination. Heterozygous HAI-1+/– mice underwent normal organ development. However, homozygous HAI-1–/– mice experienced embryonic lethality which became evident at embryonic day 10.5 postcoitum (E10.5). As early as E9.5, HAI-1–/– embryos showed growth retardation that did not reflect impaired cell proliferation but resulted instead from failed placental development and function. Histological analysis revealed severely impaired formation of the labyrinth layer, in contrast all other placental layers, such as the spongiotrophoblast layer and giant cell layer, which were formed. Our results indicate that mouse HAI-1 is essential for branching morphogenesis in the chorioallantoic placenta and lack of HAI-1 function may result in placental failure.

* Corresponding author. Mailing address: Second Department of Pathology, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan. Phone: 81 985 85 2809. Fax: 81 985 85 6003. E-mail: mejina{at}med.miyazaki-u.ac.jp.

Molecular and Cellular Biology, July 2005, p. 5687-5698, Vol. 25, No. 13
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.13.5687-5698.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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