Dmrt1 in fetal germ cell development

In the following chapters I will describe my work on the role of Dmrt1 in fetal germ cell development. In chapter two I will describe the role of Dmrt1 in regulating germ cell pluripotency and its role as a tumor suppressor. Dmrt1 mutants on the 129Sv genetic background develop teratomas at a 90% incidence. We discovered that Dmrt1 mutant germ cells failed to exit the mitotic program and failed to repress pluripotency genes OCT3/4, NANOG and SOX2. These mutant germ cells inappropriately differentiated into teratomas via an embryonal carcinoma cell intermediate. In chapter three I will describe the role of Dmrt1 in regulating meiotic initiation in females. Dmrt1 is expressed transiently in fetal oocytes and is required for efficient activation of STRA8 and for proper localization of SYCP3 and gammaH2AX onto chromosomes during meiotic prophase. This resulted in many fewer follicles in the adult ovary, but these females are fertile. ChIP revealed that the main role of DMRT1 in oocytes is to directly activate Stra8 transcription. In chapter four I will describe how genetic background modulates the phenotypes observed in Dmrt1 mutant mice. We find that Dmrt1 mutant gonads have ectopic pluripotency gene expression regardless of strain background or sex. Using ChIP-chip and ChIP-seq we discovered that DMRT1 might be recruited to DNA via KLF2, KLF4 and/or KLF5.