Abstract
Matriptase/MT-SP1 is a novel tumor-associated type II transmembrane serine protease that is highly expressed in the epidermis, thymic stroma, and other epithelia. A null mutation was introduced into the Matriptase/MT-SP1 gene of mice to determine the role of Matriptase/MT-SP1 in epidermal development and neoplasia. Matriptase/MT-SP1-deficient mice developed to term but uniformly died within 48 h of birth. All epidermal surfaces of newborn mice were grossly abnormal with a dry, red, shiny, and wrinkled appearance. Matriptase/MT-SP1-deficiency caused striking malformations of the stratum corneum, characterized by dysmorphic and pleomorphic corneocytes and the absence of vesicular bodies in transitional layer cells. This aberrant skin development seriously compromised both inward and outward epidermal barrier function, leading to the rapid and fatal dehydration of Matriptase/MT-SP1-deficient pups. Loss of Matriptase/MT-SP1 also seriously affected hair follicle development resulting in generalized follicular hypoplasia, absence of erupted vibrissae, lack of vibrissal hair canal formation, ingrown vibrissae, and wholesale abortion of vibrissal follicles. Furthermore, Matriptase/MT-SP1-deficiency resulted in dramatically increased thymocyte apoptosis, and depletion of thymocytes. This study demonstrates that Matriptase/MT-SP1 has pleiotropic functions in the development of the epidermis, hair follicles, and cellular immune system.
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Acknowledgements
We thank the NIDCR gene targeting core for blastocyst injections, Drs Henning Birkedal-Hansen, Silvio Gukind, Kenn Holmbeck, Keld Danø, and Mary Jo Danton for critically reading the manuscript, Dr Panomwat Amornphimoltam for advice on keratin immunostaining, and Dr Ulrike Lichti for advice on hair canal formation. We also thank Yamei Gao, Elizabeth Smith, Hannah Aaronson, and David Mitola for their excellent technical assistance. K List was supported by fellowships from the Danish Cancer Society and Svend Cole Frederiksen and Hustrus Foundation.
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List, K., Haudenschild, C., Szabo, R. et al. Matriptase/MT-SP1 is required for postnatal survival, epidermal barrier function, hair follicle development, and thymic homeostasis. Oncogene 21, 3765–3779 (2002). https://doi.org/10.1038/sj.onc.1205502
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DOI: https://doi.org/10.1038/sj.onc.1205502
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