Abstract
The size of the primordial follicle pool determines the reproductive potential of mammalian females, and establishment of the pool is highly dependent on specific genes expression. However, the molecular mechanisms by which the essential genes are regulated coordinately to ensure primordial follicle assembly remain a mystery. Here, we show that the small GTPase Rac1 plays an indispensable role in controlling the formation of primordial follicles in mouse ovary. Employing fetal mouse ovary organ culture system, we demonstrate that disruption of Rac1 retarded the breakdown of germline cell cysts while Rac1 overexpression accelerated the formation of primordial follicles. In addition, in vivo inhibitor injection resulted in the formation of multi-oocyte follicles. Subsequent investigation showed that Rac1 induced nuclear import of STAT3 by physical binding. In turn, nuclear STAT3 directly activated the transcription of essential oocyte-specific genes, including Jagged1, GDF9, BMP15 and Nobox. Further, GDF9 and BMP15 regulated the translation of Notch2 via mTORC1 activation in pregranulosa cells. Overexression or addition of Jagged1, GDF9 and BMP15 not only reversed the effect of Rac1 disruption, but also accelerated primordial follicle formation via Notch2 signaling activation. Collectively, these results indicate that Rac1 plays important roles as a key regulator in follicular assembly.
Highlights
In mice, primordial germ cells migrate to the urogenital ridge around embryonic day 11 (E11)[4]
We discovered that Rac[1] expressed in germ cells regulates primordial follicle formation and controls transcription of essential oocyte-enriched genes, including Jagged[1], GDF9, BMP15 and Nobox, by inducing STAT3 nuclear translocation
Results of luciferase reporter assays in 293FT cells showed that STAT3 overexpression significantly enhanced the activity of Jagged[1], GDF9, BMP15, and Nobox promoters (Fig. 4B), collectively, these results suggest that STAT3 directly targets and activates transcription of oocyte-specific genes
Summary
Primordial germ cells migrate to the urogenital ridge around embryonic day 11 (E11)[4]. We postulated that Rac[1] plays a physiological role in primordial follicle formation and modulates transcriptional activation of genes necessary for follicular assembly. We discovered that Rac[1] expressed in germ cells regulates primordial follicle formation and controls transcription of essential oocyte-enriched genes, including Jagged[1], GDF9, BMP15 and Nobox, by inducing STAT3 nuclear translocation. By regulating Jagged[1], GDF9 and BMP15, Rac[1] activates the Notch[2] signaling pathway in pregranulosa cells. These results indicate that Rac[1] is crucial for primordial follicle formation in the mouse ovary under physiological conditions
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