TSPY Expression Is Variably Altered in Transgenic Mice with Testicular Feminization1

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.

The chromosome Y-linked testis-specific protein locus TSPY1 is characteristically present in gonadoblastoma

“…Admittedly, it remains a possibility that the TSPY1 locus is present, in this case as a chromosomal segment below the resolution of interphase FISH, although the fact that TSPY1 is present in normal cells as an array of about 35 tandem repeats of the gene suggests it is unlikely [6]. In any event, recent evidence from a TSPY transgenic mouse line emphasizes that additional genes besides TSPY1 are involved in the development of GB [10,28], although the pathogenic mechanisms responsible for GB outside the setting of an intersex disorder with dysgenetic gonads are currently unknown, as are the genetic features associated with apparent progression to other germ cell and stromal tumors.…”

Testis-specific Fank1 gene in knockdown mice produces oligospermia via apoptosis

“…More than 100 genes have been identified to play important roles during spermatogenesis,12131415 but the mechanisms and key genes responsible for sperm morphogenesis are poorly understood. Fank1 is exclusively expressed in the testis from the meiosis phase to the haploid phase of spermatogenesis; therefore, it may function as a testis-specific transcription factor.…”

Transgenic Mouse Studies to Understand the Regulation, Expression and Function of the Testis-Specific Protein Y-Encoded (TSPY) Gene

“…TSPY transcripts originating from the same TSPY transcription units are frequently alternatively spliced thereby producing various TSPY isoforms of yet unknown function. Up to now, 11 different TSPY splice variants that vary in sequence and length have been identified in prostatic, testicular and testicular tumor tissues [3,7,15,17,26] and many of these are also present in the testes of TSPY transgenic mice (Figure 2; [47,50,51]). …”

“…All of these encode polymorphic TSPY isoforms harboring either the whole or part of the cyclin B binding SET/NAP domain of TSPY at their carboxyl termini [47,50,51,52]. Thus, this model can be useful in further studies for functional analyses of the different TSPY isoforms.…”