Schubert Stephanie, Kamino Kenji, Böhm Detlef, Adham Ibrahim, Engel Wolfgang, von Wasielewski Reinhard, Moharregh-Khiabani Darius, Mauceri Grazia, Vaske Bernhard, Meinhardt Andreas, Schöner Anja, Gonzalez-Fassrainer Daniela, Schmidtke Jörg
Institute of Human Genetics, Hannover Medical School, D-30625 Hannover, Germany.
Biol Reprod. 2008 Jul;79(1):125-33. doi: 10.1095/biolreprod.107.067025. Epub 2008 Apr 9.
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.
TSPY（睾丸特异性蛋白，Y染色体编码）基因在减数分裂前的生殖细胞和圆形精子细胞中表达。TSPY表达的拓扑结构和时间，以及它与TTSN家族成员的同源性，表明TSPY是生殖细胞的增殖因子。也有证据表明TSPY在睾丸癌的病因学中起作用。TSPY是GBY的候选基因，GBY是人类Y染色体上难以捉摸的性腺母细胞瘤位点，被认为使46，XY性反转女性的发育异常性腺易发生性腺母细胞瘤。我们之前已经构建了一个TSPY转基因小鼠品系（Tg(TSPY)9Jshm），该品系在小鼠Y染色体上携带大约50个拷贝的人类TSPY基因。为了阐明在完全雄激素不敏感情况下的TSPY表达，并研究TSPY在性腺肿瘤发生中的可能作用，我们现在构建了性反转的TSPY转基因Ar(Tfm)小鼠，这些小鼠对于X连锁的睾丸女性化突变（Ar(Tfm)）是半合子。我们可以表明，TSPY转录本在TSPY-Ar(Tfm)小鼠的睾丸中异常剪接，并且在一些但不是所有动物中，雄激素不敏感会上调TSPY表达。TSPY转基因小鼠的睾丸重量显著增加。在一只TSPY转基因Ar(Tfm)动物中，精子发生超过了减数分裂前期。在TSPY-Ar(Tfm)小鼠的睾丸中未发现生殖细胞起源的肿瘤。46只TSPY转基因Ar(Tfm)小鼠中有5只，31只年龄相关的NMRI-Ar(Tfm)对照中有3只发生了睾丸间质细胞瘤，而在野生型背景下年龄匹配的Ar(Tfm)小鼠（n = 44）中没有一只受到睾丸间质细胞瘤发生的影响。
