Published online before print October 2, 2008

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(American Journal of Pathology. 2008;173:1464-1475.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.071142

Defect of Hepatocyte Growth Factor Activator Inhibitor Type 1/Serine Protease Inhibitor, Kunitz Type 1 (Hai-1/Spint1) Leads to Ichthyosis-Like Condition and Abnormal Hair Development in Mice

Koki Nagaike^*, Makiko Kawaguchi^*, Naoki Takeda, Tsuyoshi Fukushima^*, Akira Sawaguchi, Kazuyo Kohama^*, Mitsuru Setoyama^¶ and Hiroaki Kataoka^*

From the Section of Oncopathology and Regenerative Biology,^* Department of Pathology, the Section of Surgical Oncology and Regulation of Organ Function, Department of Surgery, and the Departments of Anatomy and Dermatology,^¶ Faculty of Medicine, University of Miyazaki, Miyazaki, and the Center for Animal Resources and Development, Institute of Resources Development and Analysis, Kumamoto University, Kumamoto, Japan

Hepatocyte growth factor activator inhibitor type 1 (HAI-1)/serine protease inhibitor, Kunitz type 1 (SPINT1) is a membrane-bound, serine proteinase inhibitor initially identified as an inhibitor of hepatocyte growth factor activator. It also inhibits matriptase and prostasin, both of which are membrane-bound serine proteinases that have critical roles in epidermal differentiation and function. In this study, skin and hair phenotypes of mice lacking the Hai-1/Spint1 gene were characterized. Previously, we reported that the homozygous deletion of Hai-1/Spint1 in mice resulted in embryonic lethality attributable to impaired placental development. To test the role of Hai-1/Spint1 in mice, the placental function of Hai-1/Spint1-mutant mice was rescued. Injection of Hai-1/Spint1^+/+ blastocysts with Hai-1/Spint1^–/– embryonic stem cells successfully generated high-chimeric Hai-1/Spint1^–/– embryos (B6Hai-1^–/–High) with normal placentas. These embryos were delivered without apparent developmental abnormalities, confirming that embryonic lethality of Hai-1/Spint1^–/– mice was caused by placental dysfunction. However, newborn B6Hai-1^–/–High mice showed growth retardation and died by 16 days. These mice developed scaly skin because of hyperkeratinization, reminiscent of ichthyosis, and abnormal hair shafts that showed loss of regular cuticular septation. The interfollicular epidermis showed acanthosis with enhanced Akt phosphorylation. Immunoblot analysis revealed altered proteolytic processing of profilaggrin in Hai-1/Spint1-deleted skin with impaired generation of filaggrin monomers. These findings indicate that Hai-1/Spint1 has critical roles in the regulated keratinization of the epidermis and hair development.

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