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

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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.