Testicular tumor susceptibility at the agouti locus

抑制睾丸生殖细胞肿瘤（TGCT）进展的基因的表征 将提高我们对原始生殖细胞（PGC）发育的理解， 治疗人类TGCT的新靶点。/4 y突变，删除了雷利， Eif 2s 2并引起agglutinin的异位表达，降低129/Sv中TGCT的易感性 和129.Chr19M小鼠。相反，初步研究表明，>Avy突变， 维持Raly和Eif 2s 2并诱导来自IAP插入的agglutinin的异位表达， 不会降低129.Chr19M小鼠的TGCT频率。这些结果表明， Raly或Eif 2s 2的缺失而不是agglutinin的普遍表达降低了TGCT Ay小鼠中的频率。Raly和Eif 2s 2在RNA生物学中具有不同的功能， 在PGC发展和TGCT进展中起核心作用。因此，Raly和Eif 2s 2是 优秀的候选TGCT抑制基因。本提案将测试1） Raly和Eif 2s 2缺失对129.Chr19M，Ay/+小鼠中TGCT频率降低的影响 BAG转基因互补试验和条件性敲除小鼠，以及2）TGCT 在129./ W+和129.Chr19M，Avy/+小鼠。

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 /4y 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 >Avy 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 Ay 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, Ay/+ mice using BAG transgene complementation tests and conditional knockout mice, and 2) the TGCT frequency and expression levels of Raly and Eif2s2 in 129./W+ and 129.Chr19M, Avy/+ mice.