GENETIC AND DEVELOPMENTAL ANALYSIS OF MECHANISMS UNDERLYING TERATOCARCINOGENESIS IN THE MOUSE GERM CELLS.

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Testicular teratomas are congenital tumors composed of various kinds of tissues and embryonic totipotent stem cells in testes. In the 129/Sv strains susceptible to spontaneous testicular teratomas (STT), these stem cells are derived from primordial germ cells (PGC) in the fetal testes. Intra-testicular grafts of their fetal testes are differentiated experimental testicular teratomas (ETT). Ovarian teratomas (SOT) in the susceptible strains such as LT and LTXBJ are derived from the eggs that are activated parthenogenetically in ovarian follicles. Recently STT and SOT have been detected in PTEN knockout (KO) mice.Then, in order to clarify mechanisms underlying normal development and teratocarcinogenesis in germ cells, we have examined susceptible mouse strains and various KO mice. Results obtained were summarized below.1).The candidate genes responsible for ETT formation were searched by linkage tests between the strain differences of ETT incidence and SSLP of micro-satellite DNA map-mar … More kers on the 1-19 chromosomes. Novel candidate regions Ett1,Ett2 (experimental testicular teratomas 1,2) were mapped.2).Novel gene Ka (Kasumi) inducing stem cell deficiency in spermatogenesis and oogenesis, melanogenesis and erythrogenesis, was detected. Its congenic strains, 129/Sv-Ka/+ and LTXBJ-Ka/+, have been established and Ka mutation stimulated STT formation and inhibited SOT formation, respectively.3).In the PTEN KO males STT was developed and activation of P13K/Akt signaling was observed in induction of totipotency in PGCs. Inhibition of Wnt/beta-catenin signaling played important role in PGC proliferation. In oocyte specific PTEN KO females SOT was never recognized. Thus, it is suggested that SOT might be produced by different mechanisms between female PGCs and matured eggs.4).Tact1,Tact2 genes and Oxct2a,Oxct2b genes are the testis haploid germ cell-specific. Tact1/Actl7b geneis a testicular germ cell-specific intronless gene and methylation of CpG dinucleotides in its open reading frame represses its expression in somatic cells. Transient expression analysis of the mouse ornithine decarboxylase antizyme haploid- specific promorter was performed using in vivo electroporation.5).Diethylstilbestrol induces fish oocyte maturation. Less