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

被引：99

作者：

Miyauchi, Hidetaka ^{[1
,2
]}

Ohta, Hiroshi ^{[1
,2
]}

Nagaoka, So ^{[1
,2
]}

Nakaki, Fumio ^{[1
,2
]}

Sasaki, Kotaro ^{[1
,2
]}

Hayashi, Katsuhiko ^{[1
,3
,4
]}

Yabuta, Yukihiro ^{[1
,2
]}

Nakamura, Tomonori ^{[1
,2
]}

Yamamoto, Takuya ^{[5
,6
,7
]}

Saitou, Mitinori ^{[1
,2
,5
,6
]}

机构：

[1] Kyoto Univ, Grad Sch Med, Dept Anat & Cell Biol, Kyoto, Japan

[2] JST, ERATO, Kyoto, Japan

[3] JST, PRESTO, Fukuoka, Japan

[4] Kyushu Univ, Dept Dev Stem Cell Biol, Fac Med Sci, Fukuoka, Japan

[5] Kyoto Univ, Ctr iPS Cell Res & Applicat, Kyoto, Japan

[6] Kyoto Univ, Inst Integrated Cell Mat Sci, Kyoto, Japan

[7] AMED, AMED CREST, Tokyo, Japan

来源：

EMBO JOURNAL | 2017年 / 36卷 / 21期

关键词：

bone morphogenetic protein; female germ-cell fate; meiosis; primordial germ cell-like cells; retinoic acid; PLURIPOTENT STEM-CELLS; IN-VITRO; MEIOTIC INITIATION; DNA METHYLATION; SEXUAL-DIFFERENTIATION; GENE-EXPRESSION; MURINE HOMOLOG; MOUSE; MEIOSIS; SPECIFICATION;

D O I：

10.15252/embj.201796875

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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, STRAS, 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.

引用

页码：3100 / 3119

页数：20

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