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TSPY Expression Is Variably Altered in Transgenic Mice with Testicular Feminization¹

Institutes of Human Genetics,⁵ Cell and Molecular Pathology,⁶ Pathology,⁷ and Biometry,⁸ Hannover Medical School, D-30625 Hannover, Germany Institute of Human Genetics,⁹ University of Göttingen, D-37073 Göttingen, Germany Section of Endocrinology, Andrology and Internal Medicine,¹⁰ Department of Biomedical Sciences, and Master in Andrological and Human Reproduction Sciences, University of Catania, I-95123 Catania, Italy Department of Anatomy and Cell Biology,¹¹ Justus-Liebig-University of Giessen, D-35385 Giessen, Germany

ABSTRACT

TSPY (testis-specific protein, Y-encoded) genes are expressed in premeiotic germ cells and round spermatids. The topology and timing of TSPY expression, and also its homology to members of the TTSN-family, suggest that TSPY is a proliferation factor for germ cells. There is also evidence for a role of TSPY in the aetiology of testis cancer. TSPY is a candidate for GBY, the elusive gonadoblastoma locus on the human Y chromosome, which is thought to predispose dysgenetic gonads of 46, XY sex-reversed females to develop gonadoblastoma. We have previously generated a TSPY transgenic mouse line (Tg(TSPY)9Jshm) that carries approximately 50 copies of the human TSPY gene on the mouse Y chromosome. In order to elucidate TSPY expression under complete androgen insensitivity and to investigate a possible role of TSPY in gonadal tumorigenesis, we have now generated sex-reversed TSPY transgenic Ar^Tfm mice hemizygous for the X-linked testicular feminization mutation (Ar^Tfm). We can show that the TSPY transcript is aberrantly spliced in the testes of TSPY-Ar^Tfm mice, and that TSPY expression is upregulated by androgen insensitivity in some but not all animals. TSPY transgenic mice showed significantly increased testes weights. In one TSPY transgenic Ar^Tfm animal, spermatogenesis proceeded beyond meiotic prophase. No tumors of germ cell origin were found in the testes of TSPY-Ar^Tfm mice. Five out of 46 TSPY transgenic Ar^Tfm mice, and 3 out of 31 age-related NMRI-Ar^Tfm controls developed Leydig cell tumors, whereas none of the age-matched Ar^Tfm mice (n = 44) on a wild type background were affected by Leydig cell tumorigenesis.

Leydig cells, spermatogenesis, testis, testosterone, TSPY

³Current address: Center of Human Genetics, D-79100 Freiburg, Germany.

⁴Current address: Institute of Neurology, Hannover Medical School, D-30625 Hannover, Germany.

¹Supported by the Deutsche Forschungsgemeinschaft (SCHM 373/16-2 to J.S.).

Correspondence: ²Stephanie Schubert, Institute of Human Genetics, Hannover Medical School, Carl-Neuberg-Str.1, D-30625 Hannover, Germany. FAX: 0049 511 532 5865; e-mail: schubert.steffi{at}mh-hannover.de