Phenotypic Analysis of Mice Lacking the Tmprss2-Encoded Protease

Abstract

Tmprss2 encodes an androgen-regulated type II transmembrane serine protease (TTSP) expressed highly in normal prostate epithelium and has been implicated in prostate carcinogenesis. Although in vitro studies suggest protease-activated receptor 2 may be a substrate for TMPRSS2, the in vivo biological activities of TMPRSS2 remain unknown. We generated Tmprss2^−/− mice by disrupting the serine protease domain through homologous recombination. Compared to wild-type littermates, Tmprss2 ^−/− mice developed normally, survived to adulthood with no differences in protein levels of prostatic secretions, and exhibited no discernible abnormalities in organ histology or function. Loss of TMPRSS2 serine protease activity did not influence fertility, reduce survival, result in prostate hyperplasia or carcinoma, or alter prostatic luminal epithelial cell regrowth following castration and androgen replacement. Lack of an observable phenotype in Tmprss2 ^−/− mice was not due to transcriptional compensation by closely related Tmprss2 homologs. We conclude that the lack of a discernible phenotype in Tmprss2 ^−/− mice suggests functional redundancy involving one or more of the type II transmembrane serine protease family members or other serine proteases. Alternatively, TMPRSS2 may contribute a specialized but nonvital function that is apparent only in the context of stress, disease, or other systemic perturbation.

We thank Alice Davy and Josée Aubin for assistance in generating targeting vectors, Carol Ware for ES cell injections, Linda Cherepow for technical expertise in tissue acquisition and processing, Matthew Fero for numerous helpful suggestions and the construction of a mouse breeding database, and Philippe Soriano for 129S4 library and targeting vectors.

T.S.K. was supported by a postdoctoral fellowship from the Canadian Institutes for Health Research. Additional support was provided by NIH grants CA85859 and DK65204 to P.S.N.