Testicular tumor susceptibility at the agouti locus

描述(申请人提供)：描述抑制小鼠睾丸生殖细胞肿瘤(TGCT)进展的基因将提高我们对原始生殖细胞(PGC)发育的了解，并为人类TGCT的治疗提供新的靶点。A(Y)突变导致Raly和Eif2s2缺失，并导致agti的异位表达，降低了129/Sv和129/chr19M小鼠对TGCT的易感性。相反，初步研究表明，A(Vy)突变维持了Raly和Eif2s2，并诱导了IAP插入的刺鼠蛋白的异位表达，但不会降低129只Chr19M小鼠的TGCT频率。综上所述，这些结果表明，Raly或Eif2s2的缺失而不是agti的普遍表达降低了A(Y)小鼠的TGCT频率。Raly和Eif2s2在RNA生物学中都有不同的功能，在PGC的发生和TGCT的进展中起着核心作用。因此，Raly和Eif2s2是很好的候选TGCT抑制基因。这项建议将测试1)Raly和Eif2s2缺失在129.Chr19M，A(Y)/小鼠中TGCT频率降低的作用，以及2)Raly和Eif2s2在129.A(Vy)/和129.Chr19M，A(Vy)/小鼠中TGCT频率和表达水平的影响。

DESCRIPTION (provided by applicant): Characterization of genes that suppress testicular germ cell tumor (TGCT) progression in mice will improve our understanding of primordial germ cell (PGC) development and provide new targets for the treatment of TGCTs in humans. The A(y) mutation, which deletes Raly and Eif2s2 and causes the ectopic expression of agouti, decreases TGCT susceptibility in 129/Sv and 129.Chr19M mice. In contrast, preliminary studies suggest that the A(vy) mutation, which maintains Raly and Eif2s2 and induces the ectopic expression of agouti from an IAP insertion, does not decrease TGCT frequency in 129.Chr19M mice. Together these results suggest that the deletion of Raly or Eif2s2 and not the ubiquitous expression of agouti decreases TGCT frequency in A(y) mice. Both Raly and Eif2s2 have distinct functions in RNA biology, which plays a central role in PGC development and TGCT progression. Therefore, Raly and Eif2s2 are excellent candidate TGCT suppressor genes. This proposal will test 1) the contributions of the Raly and Eif2s2 deletions on the decreased TGCT frequency in 129.Chr19M, A(y)/+ mice using BAG transgene complementation tests and conditional knockout mice, and 2) the TGCT frequency and expression levels of Raly and Eif2s2 in 129.A(vy)/+ and 129.Chr19M, A(vy)/+ mice.