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

Nature. 2013 Sep 12;501(7466):222-6. doi: 10.1038/nature12417. Epub 2013 Aug 4.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation* / genetics
  • Cell Lineage* / genetics
  • Embryonic Stem Cells / cytology
  • Embryonic Stem Cells / metabolism
  • Epigenesis, Genetic
  • Female
  • Fertility
  • Gene Expression Profiling
  • Germ Cells / cytology*
  • Germ Cells / metabolism*
  • Germ Layers / cytology
  • Male
  • Mesoderm / cytology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred ICR
  • Mice, Transgenic
  • Positive Regulatory Domain I-Binding Factor 1
  • Spermatogenesis
  • Transcription Factor AP-2 / genetics
  • Transcription Factor AP-2 / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • Prdm1 protein, mouse
  • Prdm14 protein, mouse
  • Tfap2c protein, mouse
  • Transcription Factor AP-2
  • Transcription Factors
  • Positive Regulatory Domain I-Binding Factor 1

Associated data

  • GEO/GSE46855