A novel PSMA/GCPII-deficient mouse model shows enlarged seminal vesicles upon aging

Prostate-specific membrane antigen (PSMA), also known as glutamate carboxypeptidase II (GCPII), is an important diagnostic and therapeutic target in prostate cancer. PSMA/GCPII is also expressed in many healthy tissues, but its function has only been established in the brain and small intestine. Several research groups have attempted to produce PSMA/GCPII-deficient mice to study the physiological role of PSMA/GCPII in detail. The outcomes of these studies differ dramatically, ranging from embryonic lethality to production of viable PSMA/GCPII-deficient mice without any obvious phenotype.

We produced PSMA/GCPII-deficient mice (hereafter also referred as Folh1-/- mice) by TALEN-mediated mutagenesis on a C57BL/6NCrl background. Using Western blot and an enzyme activity assay, we confirmed the absence of PSMA/GCPII in our Folh1-/- mice. We performed anatomical and histopathological examination of selected tissues with a focus on urogenital system. We also examined the PSMA/GCPII expression profile within the mouse urogenital system using an enzyme activity assay and confirmed the presence of PSMA/GCPII in selected tissues by immunohistochemistry.

Our Folh1-/- mice are viable, breed normally, and do not show any obvious phenotype. Nevertheless, aged Folh1-/- mice of 69-72 weeks exhibit seminal vesicle dilation, which is caused by accumulation of luminal fluid. This phenotype was also observed in Folh1+/- mice; the overall difference between our three cohorts (Folh1-/-, Folh1+/-, and Folh1+/+) was highly significant (P < 0.002). Of all studied tissues of the mouse urogenital system, only the epididymis appeared to have a physiologically relevant level of PSMA/GCPII expression. Additional experiments demonstrated that PSMA/GCPII is also present in the human epididymis.

In this study, we provide the first evidence characterizing the reproductive tissue phenotype of PSMA/GCPII-deficient mice. These findings will help lay the groundwork for future studies to reveal PSMA/GCPII function in human reproduction.

The Prostate. 2018 Sep 05 [Epub ahead of print]

Barbora Vorlová, František Sedlák, Petr Kašpárek, Karolína Šrámková, Marek Malý, Josef Zámečník, Pavel Šácha, Jan Konvalinka

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague 6, Czech Republic., Laboratory of Transgenic Models of Diseases, Institute of Molecular Genetics of the Czech Academy of Sciences, Vestec, Czech Republic., National Institute of Public Health, Prague 10, Czech Republic., Department of Pathology and Molecular Medicine, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague 5, Czech Republic.