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

小鼠生殖细胞畸胎癌发生机制的遗传和发育分析。

基本信息

批准号：
14380381
负责人：
NOGUCHI Motoko
金额：
$ 9.6万
依托单位：
Shizuoka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

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

睾丸畸胎瘤是由睾丸内各种组织和胚胎全能干细胞组成的先天性肿瘤。在对自发性睾丸畸胎瘤(STT)易感的129/Sv株中，这些干细胞来自胎儿睾丸中的原始生殖细胞(PGC)。胎儿睾丸的睾丸内移植是分化的实验性睾丸畸胎瘤(ETT)。易感品系如LT和LTXBJ中的卵巢畸胎瘤(SOT)来源于卵泡中孤雌激活的卵子。最近在PTEN基因敲除(KO)小鼠中检测到STT和SOT。为了阐明生殖细胞正常发育和致畸的机制，我们研究了易感小鼠品系和不同的KO小鼠。主要研究结果如下：1)利用ETT发病株系差异与微卫星DNAMAR-…的SSLP连锁试验，寻找与ETT形成相关的候选基因在1-19条染色体上有更多的基因。定位了新的候选区域Ett1、Ett2(实验性睾丸畸胎瘤1、2)。2)检测到新基因KA(Kasumi)导致干细胞在精子发生和卵子发生、黑素形成和红血球发生方面的缺陷。建立了其同源菌株129/Sv-Ka/+和LTXBJ-Ka/+，KA突变分别刺激STT的形成和抑制SOT的形成。3)在PTEN KO雄株中形成STT，并观察到P13K/Akt信号的激活在诱导PGCs的全能性。抑制Wnt/β-catenin信号通路在PGC增殖中起重要作用。在卵母细胞特异性的PTEN KO雌性中，SOT从未被识别。4)Tact1、Tact2基因和Oxct2a、Oxct2b基因是睾丸单倍体生殖细胞所特有的。Tact1/Actl7b基因是睾丸生殖细胞特异的无内含子基因，其开放阅读框中CpG二核苷酸的甲基化抑制了其在体细胞中的表达。利用体内电穿孔技术对小鼠鸟氨酸脱羧酶抗酶单倍体特异性蛋白进行了瞬时表达分析。5)己烯雌酚诱导鱼卵母细胞成熟。较少