Testis

TSPY Expression Is Variably Altered in Transgenic Mice with Testicular Feminization

Abstract
TSPY genes encode the testis-specific protein, Y encoded, and 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 was proceedeing 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.

Key words: Testis • Leydig cells • Spermatogenesis • Testosterone • TSPY