Transforming Growth Factor-β Signaling Participates in the Maintenance of the Primordial Follicle Pool in the Mouse Ovary

• Published in: The Journal of biological chemistry Vol. 289; no. 12; pp. 8299 - 8311
• Main Authors: Wang, Zheng-Pin, Mu, Xin-Yi, Guo, Meng, Wang, Yi-Jing, Teng, Zhen, Mao, Guan-Ping, Niu, Wan-Bao, Feng, Li-Zhao, Zhao, Li-Hua, Xia, Guo-Liang
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21-03-2014; American Society for Biochemistry and Molecular Biology
• Subjects: Animals; Cell Growth; Cell Proliferation; Developmental Biology; Down-Regulation; Female; Gene Expression Regulation, Developmental; Male; Mechanistic Target of Rapamycin Complex 1; Mice; Mouse; Multiprotein Complexes - metabolism; Oocyte; Oocytes - growth & development; Oocytes - metabolism; Oocytes - ultrastructure; Organ Culture Techniques; Ovarian Follicle - growth & development; Ovarian Follicle - metabolism; Ovarian Follicle - ultrastructure; Ovary; Ovary - cytology; Ovary - growth & development; Ovary - metabolism; Ovary - ultrastructure; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Receptor, Transforming Growth Factor-beta Type I; Receptors, Transforming Growth Factor beta - genetics; Receptors, Transforming Growth Factor beta - metabolism; Ribosomal Protein S6 Kinases, 70-kDa - metabolism; Signal Transduction; TOR Serine-Threonine Kinases - metabolism; Transforming Growth Factor beta1 - genetics; Transforming Growth Factor beta1 - metabolism; Transforming Growth Factor-β (TGFβ); Ovary; Cell Growth; Mouse; Oocyte; Transforming Growth Factor-β (TGFβ)
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M113.532952

Physiologically, only a few primordial follicles are activated to enter the growing follicle pool each wave. Recent studies in knock-out mice show that early follicular activation depends on signaling from the tuberous sclerosis complex, the mammalian target of rapamycin complex 1 (mTORC1), phosphatase and tensin homolog deleted on chromosome 10, and phosphatidylinositol 3-kinase (PI3K) pathways. However, the manner in which these pathways are normally regulated, and whether or not TGF-β acts on them are poorly understood. So, this study aims to identify whether or not TGF-β acts on the process. Ovary organ culture experiments showed that the culture of 18.5 days post-coitus (dpc) ovaries with TGF-β1 reduced the total population of oocytes and activated follicles, accelerated oocyte growth was observed in ovaries treated with TGF-βR1 inhibitor 2-(5-chloro-2-fluorophenyl)pteridin-4-yl]pyridin-4-yl-amine (SD208) compared with control ovaries, the down-regulation of TGF-βR1 gene expression also activated early primordial follicle oocyte growth. We further showed that there was dramatically more proliferation of granulosa cells in SD208-treated ovaries and less proliferation in TGF-β1-treated ovaries. Western blot and morphological analyses indicated that TGF-β signaling manipulated primordial follicle growth through tuberous sclerosis complex/mTORC1 signaling in oocytes, and the mTORC1-specific inhibitor rapamycin could partially reverse the stimulated effect of SD208 on the oocyte growth and decreased the numbers of growing follicles. In conclusion, our results suggest that TGF-β signaling plays an important physiological role in the maintenance of the dormant pool of primordial follicles, which functions through activation of p70 S6 kinase 1 (S6K1)/ribosomal protein S6 (rpS6) signaling in mouse ovaries.
Background: Why only a few follicles are activated to enter the growing follicle pool each wave remains unclear.
Results: TGF-β regulates oocyte growth through p70 S6 kinase 1/ribosomal protein S6 signaling.
Conclusion: TGF-β participates in maintenance of the primordial follicle pool.
Significance: Learning how TGF-β acts on primordial follicle growth.