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

小鼠原始生殖细胞睾丸畸胎瘤诱导机制的遗传学和发育生物学分析

• 批准号: 12680809
• 负责人: NOGUCHI Motoko
• 金额: $ 2.3万
• 依托单位: SHIZUOKA UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12680809/
• 关键词: Testicular teratomas; Mouse embryo; Primordial germ cells; ter (teratoma) gene; ett1 (experimental testicular teratomas 1) gene; Germ-cell growth factor; Gonadal somatic cells; Apoptosis; マウス; テラトーマ原因遺伝子; 染色体マッピング; 胎仔精巣; 生殖細胞特異抗原; ter変異遺伝子

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.

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。在易患自发性睾丸畸胎瘤 (STT) 的 129/Sv 品系及其亚系中，这些干细胞源自胎儿睾丸中的原始生殖细胞 (PGC)。 ter（畸胎瘤，Chr.18）突变会导致 ter/ter 男性中 PGC 缺乏和 STT 发生率高。 129/Sv 胎儿睾丸移植物中约 90% 分化为实验性睾丸畸胎瘤 (ETT)。我们建立的ter同类系中的所有ter/ter雄性均具有PGC缺陷的小睾丸，而没有STT。然后，在该项目中，为了阐明小鼠睾丸畸胎癌发生的机制，检查了ter突变、胎儿睾丸体细胞和PGC的功能，并从遗传学上搜索了负责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ter同系小鼠胎儿卵巢和睾丸体细胞的条件培养基(CM)分析ter基因诱导PGC缺陷的功能。结论是，一种具有可溶性和膜结合型的新型 TER 相关 PGC 生长因子（称为 TER 因子，TERF）通过在发育阶段抑制 PGC 细胞凋亡来支持 PGC 存活，并且它是由卵巢和睾丸体细胞产生的。还得出结论，ter/ter体细胞产生默认类型的TERF，导致具有正常生存能力和增殖能力的ter/terPGCs凋亡性死亡，以及ter/term雄性和雌性的不育。2)129/Sv-+/ter(+/+)小鼠的胎儿睾丸体细胞可能在诱导初始阶段发挥关键作用。 ETT.3)。绘制了负责 ETT 的新基因（指定为 ett1，实验性睾丸畸胎瘤 1）。讨论了睾丸终止在畸胎癌发生中的作用。

项目成果

T.Ueda,K.Abe,M.Noguchi,H.Sasaki et al: "The paternal methylation imprint of the mouse H19 locus is acquired in the gonocyte stage during foetal testis development."Genes to Cells. 5(8). 649-659 (2000)

T.Ueda、K.Abe、M.Noguchi、H.Sasaki 等人：“小鼠 H19 基因座的父系甲基化印记是在胎儿睾丸发育过程中的生殖母细胞阶段获得的。”基因到细胞。

Testicular somatic cells are responsible for experimental terato-carcinogenesis of primordial germ cells in reconstituted testes.

睾丸体细胞负责重建睾丸中原始生殖细胞的实验性畸胎癌发生。

• 发表时间: 2000
• 期刊: Journal of Reproduction and Development 46
• 作者: Noguchi;M.;Niwa;K.;Kasai;T.;Tsunesada;M.;Sasaoka;Y.;Kusakabe;M.
• 通讯作者: M.

S.Takabayashi, M.Nozaki, K.Ishikawa, M.Noguchi: "The ter/ter gonadal somatic cells cause apoptosis inter/ter primordial germ cells (PG-Cs) with normal survivability and proliferation ability in the mouse : Evidence from PGC-somatic cell "exchange-co-cultu

S.Takabayashi、M.Nozaki、K.Ishikawa、M.Noguchi：“在小鼠中，三性腺体细胞导致具有正常生存能力和增殖能力的原始生殖细胞 (PG-C) 之间的凋亡：来自 PGC 的证据

S.Takabayashi, T.Tokumoto, M.Noguchi, et al.: "Novel growth factor supporting survival of murine primordial germ cells : Evidence from conditioned medium of ter fetal gonadal somatic cells"Molecular Reproduction and Development. 60(3). 384-396 (2001)

S.Takabayashi、T.Tokumoto、M.Noguchi 等人：“支持小鼠原始生殖细胞存活的新型生长因子：来自胎儿性腺体细胞条件培养基的证据”分子生殖和发育。

Novel growth factor supporting survival of murine primordial germ cells: evidence from conditioned medium of ter fetal gonadal somatic cells

• DOI: 10.1002/mrd.1101
• 发表时间: 2001-11
• 期刊: Molecular Reproduction and Development
• 影响因子: 2.5
• 作者: Shuji Takabayashi;Yumiko Sasaoka;M. Yamashita;T. Tokumoto;K. Ishikawa;M. Noguchi