GENETICS AND DEVELOPMENTAL BIOLOGICAL ANALYSIS OF MECHANISMS INDUCING TESTICULAR TERATOCARCINOGENESIS IN PRIMORDIAL GERM CELLS IN MICE

哺乳动物睾丸畸胎瘤是由睾丸内多种组织和胚胎多能干细胞组成的先天性肿瘤。在自发性睾丸畸胎瘤（STT）易感的129/Sv毒株及其亚系中，这些干细胞来源于胎儿睾丸中的原始生殖细胞（PGC）。ter（畸胎瘤，Chr. 18）突变在ter/ter男性中导致PGC缺乏和STT的高发。129/Sv胎儿睾丸移植约90%分化为实验性睾丸畸胎瘤（ETT）。在我们所建立的同系株中，所有的雄性都有PGC缺陷的小睾丸，没有STT。然后，在本项目中，为了阐明小鼠睾丸畸胎瘤发生的机制，我们检测了ter突变、胎儿睾丸体细胞和PGCs的功能，并从遗传学上寻找了ETT的候选基因。所得结果总结如下1)。采用“PGC-体细胞共培养系统”和条件培养基（CM），对ter基因诱导PGC缺陷的功能进行了分析。由此可见，一种新型的TER相关的PGC生长因子（被称为TER因子，TERF）具有可溶性和膜结合型，通过抑制PGC在发育阶段的凋亡来支持PGC存活，该因子是由卵巢和睾丸体细胞产生的。研究还发现，ter/ter体细胞产生一种默认类型的TERF，导致ter/terPGCs的凋亡死亡，ter/terPGCs具有正常的生存和增殖能力，ter/terPGCs雌雄不育。129/Sv-+/ter（+/+）小鼠的胎儿睾丸体细胞可能在et诱导的初始阶段起关键作用(s)。一个新的基因（指定为ett1，实验性睾丸畸胎瘤1）负责ETT被定位。本文讨论了睾丸畸胎瘤发生过程中三章子化的作用。

Testicular teratomas in mammals are congenital tumors composed of various kinds of tissues and embryonic multi-potent stem cells in testes. In the 129/Sv strain and its sublines susceptible to spontaneous testicular teratomas (STT), these stem cells are derived from primordial germ cells (PGC) in the fetal testes. The ter (teratoma, Chr. 18) mutation causes both the PGC deficiency and high incidence of STT in ter/ter males. About 90% of the grafts of the 129/Sv fetal testes differentiated experimental testicular teratomas (ETT). All of ter/ter males in ter congenic strains established by us have PGC deficient small testes without STT.Then, in this project to clarify mechanisms underlying testicular teratocarcinogenesis in mice, the functions of the ter mutation, fetal testicular somatic cells and PGCs were examined and candidate genes responsible for ETT was searched genetically. Results obtained were summarized below.1).The function of the ter gene inducing PGC deficiency was analyzed using "PGC-somatic cells co-culture systems" and conditioned medium (CM) from fetal ovarian and testicular somatic cells in the ter congenic mice. It is concluded that a novel ter-related PGC growth factor (designated as TER Factor, TERF) with soluble and membrane-bounded types supports PGC survival by inhibiting apoptosis in PGCs through developmental stages and that it is produced by ovarian and testicular somatic cells. It is also concluded that ter/ter somatic cells produce a default type of TERF, resulting in apoptotic death of ter/terPGCs with normal survivability and proliferation ability and sterility of ter/termales and females.2).Fetal testicular somatic cells in 129/Sv-+/ter(+/+) mice may play key role(s) in the initial phase of induction of ETT.3).A novel gene (designated as ett1, experimental testicular teratomas 1) responsible for ETT was mapped. Function of the ter nutation in testicular teratocarcinogenesis was discussed.