TY - JOUR
T1 - Bone morphogenetic protein and retinoic acid synergistically specify female germ-cell fate in mice
AU - Miyauchi, Hidetaka
AU - Ohta, Hiroshi
AU - Nagaoka, So
AU - Nakaki, Fumio
AU - Sasaki, Kotaro
AU - Hayashi, Katsuhiko
AU - Yabuta, Yukihiro
AU - Nakamura, Tomonori
AU - Yamamoto, Takuya
AU - Saitou, Mitinori
N1 - Funding Information:
We thank K. Abe, T. Noce, and Mitsubishi Chemical Corporation for providing us with the mVH-RFP mice. We are grateful to the members of the Saitou Laboratory for their discussion of this study. We thank Y. Nagai, R. Kabata, N. Konishi, Y. Sakaguchi, and M. Kawasaki of the Saitou Laboratory, and T. Sato and M. Kabata of the Yamamoto Laboratory for their technical assistance. This work was supported in part by JST-ERATO to M.S. (JPMJER1104) and by a Grant-in-Aid for Specially Promoted Research from JSPS to M.S. (17H06098) and by a Grant-in-Aid for JSPS to H.O. (JP15H05636). H.M. is a fellow of the Takeda Science Foundation.
Publisher Copyright:
© 2017 The Authors
PY - 2017/11/2
Y1 - 2017/11/2
N2 - 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.
AB - 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.
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U2 - 10.15252/embj.201796875
DO - 10.15252/embj.201796875
M3 - Article
C2 - 28928204
AN - SCOPUS:85030090275
SN - 0261-4189
VL - 36
SP - 3100
EP - 3119
JO - EMBO Journal
JF - EMBO Journal
IS - 21
ER -