Testicular tumor susceptibility at the agouti locus

描述（由申请人提供）：在小鼠中抑制睾丸生殖细胞肿瘤（TGCT）进展的基因特征将提高我们对原始生殖细胞（PGC）发育的理解，并为治疗人类TGCT提供新的靶点。A(y)突变删除了Raly和Eif2s2，导致agouti异位表达，降低了129/Sv和129的TGCT易感性。Chr19M老鼠。相比之下，初步研究表明，A（vy）突变维持了Raly和Eif2s2，并诱导了IAP插入agouti的异位表达，但并未降低129的TGCT频率。Chr19M老鼠。总之，这些结果表明，在A(y)小鼠中，rally或Eif2s2的缺失而不是agouti的普遍表达降低了TGCT频率。Raly和Eif2s2在RNA生物学中具有不同的功能，在PGC的发生和TGCT的进展中起着核心作用。因此，Raly和Eif2s2是TGCT极好的候选抑制基因。本提案将测试1)129中Raly和Eif2s2缺失对TGCT频率降低的贡献。使用BAG转基因互补试验的Chr19M， A(y)/+小鼠和条件敲除小鼠；2)129例中Raly和Eif2s2的TGCT频率和表达水平。A(vy)/+和129。Chr19M， A(vy)/+小鼠。

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.