TY - JOUR
T1 - Induction of mouse germ-cell fate by transcription factors in vitro
AU - Nakaki, Fumio
AU - Hayashi, Katsuhiko
AU - Ohta, Hiroshi
AU - Kurimoto, Kazuki
AU - Yabuta, Yukihiro
AU - Saitou, Mitinori
N1 - Funding Information:
Acknowledgements We thank A. Bradley, A. Smith, G. Guo, H. Niwa and G. Nagamatsu for providing plasmids. We are grateful to the Center for Anatomical Studies (Graduate School of Medicine, Kyoto University) for performing the histological analyses. We thankM.Yamajifor adviceand T.Morifor encouragement.F.N.isaJapanSocietyfor the Promotion of Science (JSPS) Research Fellow. This study was supported in part by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology of Japan; by JST-CREST/ERATO; by the Takeda Science Foundation; and by the Academia for Repro-regenerative Medicine.
PY - 2013
Y1 - 2013
N2 - 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 oogenesis, 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.
AB - 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 oogenesis, 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.
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U2 - 10.1038/nature12417
DO - 10.1038/nature12417
M3 - Article
C2 - 23913270
AN - SCOPUS:84884160850
SN - 0028-0836
VL - 501
SP - 222
EP - 226
JO - Nature
JF - Nature
IS - 7466
ER -