Details

Autor(en) / Beteiligte

• Miyauchi, Hidetaka
• Ohta, Hiroshi
• Nagaoka, So
• Nakaki, Fumio
• Sasaki, Kotaro
• Hayashi, Katsuhiko
• Yabuta, Yukihiro
• Nakamura, Tomonori
• Yamamoto, Takuya
• Saitou, Mitinori

Titel

Bone morphogenetic protein and retinoic acid synergistically specify female germ‐cell fate in mice

Ist Teil von

• The EMBO journal, 2017-11, Vol.36 (21), p.3100-3119

Ort / Verlag

England: Blackwell Publishing Ltd

Erscheinungsjahr

2017

Link zum Volltext

Quelle

Wiley-Blackwell Journals

Beschreibungen/Notizen

• The mechanism for sex determination in mammalian germ cells remains unclear. Here, we reconstitute the female sex determination in mouse germ cells in vitro under a defined condition without the use of gonadal somatic cells. We show that retinoic acid (RA) and its key effector, STRA8, are not sufficient to induce the female germ‐cell fate. In contrast, bone morphogenetic protein (BMP) and RA synergistically induce primordial germ cells (PGCs)/PGC‐like cells (PGCLCs) derived from embryonic stem cells (ESCs) into fetal primary oocytes. The induction is characterized by entry into the meiotic prophase, occurs synchronously and recapitulates cytological and transcriptome progression in vivo faithfully. Importantly, the female germ‐cell induction necessitates a proper cellular competence—most typically, DNA demethylation of relevant genes—which is observed in appropriately propagated PGCs/PGCLCs, but not in PGCs/PGCLCs immediately after induction. This provides an explanation for the differential function of BMP signaling between PGC specification and female germ‐cell induction. Our findings represent a framework for a comprehensive delineation of the sex‐determination pathway in mammalian germ cells, including humans. Synopsis In vitro reconstitution of female sex determination using ESC‐derived germ cells demonstrates requirement of integrated signaling inputs and epigenetic background for fetal oocyte induction. Female mouse germ‐cell sex specification is reconstituted under a defined set of conditions. Retinoic acid (RA) and its effector STRA8 are not sufficient to induce the fetal oocyte phenotype from ESC‐derived primordial germ cells. Bone morphogenetic protein (BMP) and RA act synergistically to instruct female germ‐cell fate. Cellular competence for acquiring female germ‐cell fate includes DNA demethylation of key genes. In vitro reconstitution of female sex determination using ESC‐derived germ cells demonstrates requirement of integrated signaling and epigenetic background for fetal oocyte induction.