Sexual Fate Change of XX Germ Cells Caused by the Deletion of SMAD4 and STRA8 Independent of Somatic Sex Reprogramming.
The differential programming of sperm and eggs in gonads is a fundamental topic in reproductive biology. Although the sexual fate of germ cells is believed to be determined by signaling factors from sexually differentiated somatic cells in fetal gonads, the molecular mechanism that determines germ cell fate is poorly understood. Herein, we show that mothers against decapentaplegic homolog 4 (SMAD4) in germ cells is required for female-type differentiation. Germ cells in Smad4-deficient ovaries respond to retinoic acid signaling but fail to undergo meiotic prophase I, which coincides with the weaker expression of genes required for follicular formation, indicating that SMAD4 signaling is essential for oocyte differentiation and meiotic progression. Intriguingly, germline-specific deletion of Smad4 in Stra8-null female germ cells resulted in the up-regulation of genes required for male gonocyte differentiation, including Nanos2 and PLZF, suggesting the initiation of male-type differentiation in ovaries. Moreover, our transcriptome analyses of mutant ovaries revealed that the sex change phenotype is achieved without global gene expression changes in somatic cells. Our results demonstrate that SMAD4 and STRA8 are essential factors that regulate the female fate of germ cells.
Department of Genetics, Sokendai, Mishima, Japan.|Division of Mammalian Development, National Institute of Genetics, Mishima, Japan.
Quan
Q
Wu
Department of Genetics, Sokendai, Mishima, Japan.|Division of Mammalian Development, National Institute of Genetics, Mishima, Japan.
Kurumi
K
Fukuda
Division of Mammalian Development, National Institute of Genetics, Mishima, Japan.
Yuzuru
Y
Kato
Division of Mammalian Development, National Institute of Genetics, Mishima, Japan.
Zhi
Z
Zhou
Faculty of Health Sciences, University of Macau, Macau SAR, China.
Chu-Xia
CX
Deng
Department of Genetics, Sokendai, Mishima, Japan.|Division of Mammalian Development, National Institute of Genetics, Mishima, Japan.|Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan.
Yumiko
Y
Saga
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D002470:Cell Survival; D002478:Cells, Cultured; D005260:Female; D017353:Gene Deletion; D015870:Gene Expression; D008297:Male; D008540:Meiosis; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D009865:Oocytes / Q000502:physiology*; D010053:Ovary / Q000166:cytology / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D019849:Sex Determination Processes; D015398:Signal Transduction; D051901:Smad4 Protein / Q000235:genetics* / Q000378:metabolism; D014212:Tretinoin / Q000502:physiology; D014960:X Chromosome / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; C477341:Nanos2 protein, mouse; D016601:RNA-Binding Proteins; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; C102019:Stra8 protein, mouse; D014212:Tretinoin