Induction of mouse germ-cell fate by transcription factors in vitro

Expression of the three transcription factors BLIMP1, PRDM14 and TFAP2C, or of PRDM14 alone, converts epiblast-like cells into primordial germ cell (PGC)-like cells; the transcription-factor-induced PGC-like cells acquire key transcriptome and epigenetic reprogramming in PGCs, and contribute to spermatogenesis and fertile offspring. A new study by Mitinori Saitou and colleagues reveals that expression of three transcription factors (Blimp1, Prdm14 and Tfap2c) in epiblast-like cells efficiently converts them into primordial germ cell (PGC)-like cells. In these conditions, the mesodermal program that accompanies PGC specification in vivo and in vitro by cytokines is bypassed — culture systems reported previously had included cytokines as well as transcription factors. The authors also show that transcription-factor-induced PGC-like cells contribute to spermatogenesis and fertile offspring. The germ-cell lineage ensures the continuity of life through the generation of male and female gametes, which unite to form a totipotent zygote. We have previously demonstrated that, by using cytokines, embryonic stem cells and induced pluripotent stem cells can be induced into epiblast-like cells (EpiLCs) and then into primordial germ cell (PGC)-like cells with the capacity for both spermatogenesis and oogenesis1,2, creating an opportunity for understanding and regulating mammalian germ-cell development in both sexes in vitro. Here we show that, without cytokines, simultaneous overexpression of three transcription factors, Blimp1 (also known as Prdm1), Prdm14 and Tfap2c (also known as AP2γ), directs EpiLCs, but not embryonic stem cells, swiftly and efficiently into a PGC state. Notably, Prdm14 alone, but not Blimp1 or Tfap2c, suffices for the induction of the PGC state in EpiLCs. The transcription-factor-induced PGC state, irrespective of the transcription factors used, reconstitutes key transcriptome and epigenetic reprogramming in PGCs, but bypasses a mesodermal program that accompanies PGC or PGC-like-cell specification by cytokines including bone morphogenetic protein 4. Notably, the transcription-factor-induced PGC-like cells contribute to spermatogenesis and fertile offspring. Our findings provide a new insight into the transcriptional logic for PGC specification, and create a foundation for the transcription-factor-based reconstitution and regulation of mammalian gametogenesis.