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各种组织和胚胎多能干细胞组成的先天性肿瘤。在129/Sv品系及其对自发性睾丸畸胎瘤（STT）易感的亚系中，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，第18条）突变导致PGC缺乏和ter/ter男性STT的高发病率。129/Sv胎儿睾丸移植物中约90%分化为实验性睾丸畸胎瘤（ETT）。本研究通过对小鼠睾丸癌发生机制的研究，探讨了ter突变、胚胎睾丸体细胞和PGCs的功能，并从遗传学角度寻找了与ETT相关的候选基因。1）利用“PGC-体细胞共培养系统”和来自胚胎卵巢和睾丸体细胞的条件培养基（CM），对ter基因诱导PGC缺陷的功能进行了分析。它的结论是一种新的TER相关的PGC生长因子（指定为TER因子，TERF）与可溶性和膜结合型支持PGC的生存通过抑制PGC的细胞凋亡，通过发育阶段，它是由卵巢和睾丸体细胞产生。129/Sv-+/ter（+/+）小鼠的胚胎睾丸体细胞可能在ETT的诱导过程中起关键作用。3）一个新的基因（命名为ett 1，实验睾丸畸胎瘤1）负责ETT的映射。本文还讨论了睾丸章动在睾丸畸胎癌发生中的作用。

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.