Dataset Information

Rac1 modulates the formation of primordial follicles by facilitating STAT3-directed Jagged1, GDF9 and BMP15 transcription in mice.

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.

SUBMITTER: Zhao L

PROVIDER: S-EPMC4822123 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Rac1 modulates the formation of primordial follicles by facilitating STAT3-directed Jagged1, GDF9 and BMP15 transcription in mice.

Zhao Lihua L Du Xinhua X Huang Kun K Zhang Tuo T Teng Zhen Z Niu Wanbao W Wang Chao C Xia Guoliang G

Scientific reports 20160406

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 ...[more]

PMID: 27050391

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Project description:Mouse oocytes control cumulus cell metabolic processes that are deficient in the oocytes themselves and this delegation is necessary for oocyte development. Oocyte-derived bone morphogenetic factor 15 (BMP15) and growth differentiation factor 9 (GDF9) appear to be key regulators of follicular development. The effect of these factors on cumulus cell function before the preovulatory surge of luteinizing hormone (LH) was assessed by analysis of the transcriptomes of cumulus cells from wildtype (WT), Bmp15-/-, and Bmp15-/- Gdf9+/- double mutant (DM) mice using microarray analysis. The biological themes associated with the most highly-affected transcripts were identified using bioinformatic approaches, IPA and GenMAPP/MAPPFinder. There were 5,332, 7,640, and 2,651 transcripts identified to be significantly changed in the comparisons of Bmp15-/- vs. WT, DM vs. WT, and DM vs. Bmp15-/- respectively by the criteria of FC (fold change) p <0.01. Among theses changed transcripts, 744 were commonly changed in all three pair-wise comparisons, and hence were considered to be the most highly affected transcripts by mutation of Bmp15 and Gdf9. IPA Analyses revealed that metabolism was the major theme associated with the most highly-changed transcripts: glycolysis and sterol biosynthesis were the two most significantly affected pathways. Most of the transcripts encoding enzymes for sterol biosynthesis were down-regulated in both mutant cumulus cells and in WT cumulus cell after oocytectomy. Similarly, there was a reduction of de novo-synthesized cholesterol in these cumulus cells. This suggests that oocytes regulate cumulus cell metabolism, particularly sterol biosynthesis, by promoting the expression of corresponding transcripts. Furthermore, in WT-mice, Mvk, Pmvk, Fdps, Sqle, Cyp51, Sc4mol, and Ebp, which encode enzymes in the sterol biosynthetic pathway, were found to be expressed robustly in cumulus cells, but expression was barely detectable in oocytes. Levels of de novo-synthesized cholesterol were significantly higher in cumulusâenclosed oocytes than denuded oocytes. These results indicate that mouse oocytes are deficient in their ability to synthesize cholesterol and require cumulus cells to provide them with products of the sterol biosynthetic pathway. Oocyte-derived BMP15 and GDF9 may promote this metabolic pathway in cumulus cells as compensation for their own deficiencies. Experiment Overall Design: Three sets of independent cumulus cell samples were collected for each genotype (wild type, Bmp15-/-, and Bmp15-/-Gdf9+/-) of mice, and were used for the array study as shown below. Experiment Overall Design: Array Genotype Sample Experiment Overall Design: GC_430_2_GES05_0161_033105_1.CEL WT 1 Experiment Overall Design: GC_430_2_GES05_0162_033105_1.CEL WT 2 Experiment Overall Design: GC_430_2_GES05_0163_033105_1.CEL WT 3 Experiment Overall Design: GC_430_2_GES05_0164_033105_1.CEL Bmp15-/- 4 Experiment Overall Design: GC_430_2_GES05_0165_033105_1.CEL Bmp15-/- 5 Experiment Overall Design: GC_430_2_GES05_0166_033105_1.CEL Bmp15-/- 6 Experiment Overall Design: GC_430_2_GES05_0167_033105_1.CEL DM 7 Experiment Overall Design: GC_430_2_GES05_0168_033105_1.CEL DM 8 Experiment Overall Design: GC_430_2_GES05_0169_033105_1.CEL DM 9

Project description:Mouse oocytes control cumulus cell metabolic processes that are deficient in the oocytes themselves and this delegation is necessary for oocyte development. Oocyte-derived bone morphogenetic factor 15 (BMP15) and growth differentiation factor 9 (GDF9) appear to be key regulators of follicular development. The effect of these factors on cumulus cell function before the preovulatory surge of luteinizing hormone (LH) was assessed by analysis of the transcriptomes of cumulus cells from wildtype (WT), Bmp15-/-, and Bmp15-/- Gdf9+/- double mutant (DM) mice using microarray analysis. The biological themes associated with the most highly-affected transcripts were identified using bioinformatic approaches, IPA and GenMAPP/MAPPFinder. There were 5,332, 7,640, and 2,651 transcripts identified to be significantly changed in the comparisons of Bmp15-/- vs. WT, DM vs. WT, and DM vs. Bmp15-/- respectively by the criteria of FC (fold change) p <0.01. Among theses changed transcripts, 744 were commonly changed in all three pair-wise comparisons, and hence were considered to be the most highly affected transcripts by mutation of Bmp15 and Gdf9. IPA Analyses revealed that metabolism was the major theme associated with the most highly-changed transcripts: glycolysis and sterol biosynthesis were the two most significantly affected pathways. Most of the transcripts encoding enzymes for sterol biosynthesis were down-regulated in both mutant cumulus cells and in WT cumulus cell after oocytectomy. Similarly, there was a reduction of de novo-synthesized cholesterol in these cumulus cells. This suggests that oocytes regulate cumulus cell metabolism, particularly sterol biosynthesis, by promoting the expression of corresponding transcripts. Furthermore, in WT-mice, Mvk, Pmvk, Fdps, Sqle, Cyp51, Sc4mol, and Ebp, which encode enzymes in the sterol biosynthetic pathway, were found to be expressed robustly in cumulus cells, but expression was barely detectable in oocytes. Levels of de novo-synthesized cholesterol were significantly higher in cumulus–enclosed oocytes than denuded oocytes. These results indicate that mouse oocytes are deficient in their ability to synthesize cholesterol and require cumulus cells to provide them with products of the sterol biosynthetic pathway. Oocyte-derived BMP15 and GDF9 may promote this metabolic pathway in cumulus cells as compensation for their own deficiencies. Keywords: Gdf9, Bmp15, cumulus cells, transcriptome, metabolism, sterol biosynthesis, genotype comparison, microarray, ingenuity pathways analyses.

Dataset Information

Rac1 modulates the formation of primordial follicles by facilitating STAT3-directed Jagged1, GDF9 and BMP15 transcription in mice.

Publications

Rac1 modulates the formation of primordial follicles by facilitating STAT3-directed Jagged1, GDF9 and BMP15 transcription in mice.

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