The role of the PGC master regulators Blimp1, Prdm14 and Tfap2c on the licensing of germ cells - control of pluripotency and channeling into unipotency

PGC 主调节因子 Blimp1、Prdm14 和 Tfap2c 在生殖细胞许可中的作用 - 控制多能性和引导至单能性

• 批准号: 284859850
• 负责人: Professor Dr. Hubert Schorle
• 金额: --
• 依托单位: Institut für Pathologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/284859850?language=en
• 关键词: role; PGC; master; regulators; Blimp1

Germ cells propagate the species. In mammals, germ cells are specified as primpordial germ cells (PGCs) in the early embryo. They migrate to the gonads where they differentiate further to form egg and sperm. In this process, pluripotent cells of the epiblast give rise to latent pluripotent cells (PGCs), which are channeled, into unipotency (egg and sperm). The control of the latent pluripotency and the channeling into unipotency is a poorly understood process. The fact that perturbations of the molecular cascades lead to sterility and/or germ cell tumors demonstrates that more knowledge about this process is mandatory.We propose to analyze germ cell specific gain of function transgenic mice overexpressing the germ cell specifiying genes Tfap2c, Blimp1 and Prdm14. We will analyze the gonads at various times during development and will bring PGCs in culture to derive embryonic germ cells. We envision that the transgenes allow for prolonged derivation of EG cells (in wildtype only up to day E 10.5), which will indicate a perturbation in canalization into unipotency. This defect might lead to the development of germ cell tumors, which, in the human situation are hallmarked by persistent expression of TFAP2C and BLIMP1. PRDM14 has been implicated in germ cell tumors by a GWAS study recently. We hypothesize, that each transgene will elicit a rather specific change in gene expression leading to a different type of tumor. In addition, we will transplant the EG-cells under the skin and monitor tumor formation. This will be compared to the tumorigenesis in the testes and will allow a comparison of the tumor-microenvironment (somatic vs. testes). The application is based on the impression of a recent sabbatical. The experiments might appear ambitious, but the applicant will cooperate with the ex-sabbatical lab of Prof. Dr. D. Page (MIT) in terms of germ cell development, and with Prof. Dr. D. deRooij (who was also visiting scientist at the Page lab at this time) to achieve all goals described.

生殖细胞繁殖物种。在哺乳动物中，生殖细胞在早期胚胎中被指定为原胞生殖细胞（PGCs）。它们迁移到性腺，在那里它们进一步分化形成卵子和精子。在这个过程中，上胚层的多能细胞产生潜伏多能细胞（PGC），这些细胞被引导成单能性（卵子和精子）。控制潜在的多能性和引导成单能性是一个知之甚少的过程。事实上，扰动的分子级联导致不育和/或生殖细胞肿瘤表明，更多的知识，这个过程是mandatory.We建议分析生殖细胞特异性增益的功能转基因小鼠过表达的生殖细胞特异性基因Tfap 2c，Blimp 1和Prdm 14。我们将在发育过程中的不同时间分析性腺，并将PGCs培养以获得胚胎生殖细胞。我们设想转基因允许EG细胞的延长衍生（在野生型中仅直到E10.5天），这将表明在通向单能性中的扰动。这种缺陷可能导致生殖细胞肿瘤的发展，在人类情况下，其特征是TFAP 2C和BLIMP 1的持续表达。最近，GWAS研究发现PRDM 14与生殖细胞肿瘤有关。我们假设，每个转基因将引发基因表达的一个相当具体的变化，导致不同类型的肿瘤。此外，我们将把EG细胞移植到皮肤下，并监测肿瘤的形成。这将与睾丸中的肿瘤发生进行比较，并将允许比较肿瘤微环境（体细胞与睾丸）。申请是基于最近休假的印象。这些实验可能看起来雄心勃勃，但申请人将与D教授的前休假实验室合作。Page教授（麻省理工学院）在生殖细胞发育方面的研究，以及与D。deRooij（当时他也是Page实验室的访问科学家）实现了所有描述的目标。