A Signaling Principle for the Specification of the Germ Cell Lineage in Mice

Specification of the germ cell lineage is vital to development and heredity. In mice, the germ cell fate is induced in pluripotent epiblast cells by signaling molecules, yet the underlying mechanism remains unknown. Here we demonstrate that germ cell fate in the epiblast is a direct consequence of B...

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Bibliographic Details
Published in:Cell 2009-05, Vol.137 (3), p.571-584
Main Authors: Ohinata, Yasuhide, Ohta, Hiroshi, Shigeta, Mayo, Yamanaka, Kaori, Wakayama, Teruhiko, Saitou, Mitinori
Format: Article
Language:English
Subjects:
Animals
Bone Morphogenetic Protein 4 - physiology
Bone Morphogenetic Proteins - physiology
Cell Differentiation - physiology
Cell Lineage - physiology
DEVBIO
Embryo, Mammalian - cytology
Embryo, Mammalian - embryology
Embryo, Mammalian - physiology
Germ Cells - cytology
Germ Cells - physiology
Male
Mesoderm - cytology
Mesoderm - physiology
Mice
Mice, Knockout
Mice, Transgenic
Positive Regulatory Domain I-Binding Factor 1
Signal Transduction - physiology
Stem Cells - cytology
Stem Cells - physiology
STEMCELL
Testis - cytology
Testis - physiology
Transcription Factors - physiology
Wnt Proteins - physiology
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Summary:Specification of the germ cell lineage is vital to development and heredity. In mice, the germ cell fate is induced in pluripotent epiblast cells by signaling molecules, yet the underlying mechanism remains unknown. Here we demonstrate that germ cell fate in the epiblast is a direct consequence of Bmp4 signaling from the extraembryonic ectoderm (ExE), which is antagonized by the anterior visceral endoderm (AVE). Strikingly, Bmp8b from the ExE restricts AVE development, thereby contributing to Bmp4 signaling. Furthermore, Wnt3 in the epiblast ensures its responsiveness to Bmp4. Serum-free, defined cultures revealed that, in response to Bmp4, competent epiblast cells uniformly expressed key transcriptional regulators Blimp1 and Prdm14 and acquired germ-cell properties, including genome-wide epigenetic reprogramming, in an orderly fashion. Notably, the induced cells contributed to both spermatogenesis and fertility of offspring. By identifying a signaling principle in germ cell specification, our study establishes a robust strategy for reconstituting the mammalian germ cell lineage in vitro.
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2009.03.014