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

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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.