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Published on: September 19, 2025
P65 Targets FGFR1 to Regulate the Survival of Ovarian Granulosa Cells
Xiaolong Yuan1, Zhonghui Li2,3, Yaru Kong4
1National Engineering Research Center for Swine Breeding Industry, Guangdong Provincial Key Lab of Agro-Animal Genomics and Molecular Breeding, College of Animal Science, South China Agricultural University, Guangzhou 510642, China. yxl@scau.edu.cn.
Abstract:
In female mammals, the abnormal apoptosis of ovarian granulosa cells (GCs) impairs follicular development and causes reproductive dysfunction. Many studies have indicated that the FGFR1 gene of the PI3K signaling pathway and the p65 subunit of the transcription factor NF-κB may regulate the proliferation and apoptosis of GCs involved in follicular development. However, little is known about whether p65 regulates the transcription of FGFR1, as well as the biological effects of p65 and FGFR1 on the survival of GCs and follicular development. In porcine follicles and GCs, we found that p65 and FGFR1 were exclusively expressed in the GCs of follicles, and the mRNA and protein levels of p65 and FGFR1 significantly increased from small to large follicles. Both p65 and FGFR1 were found to activate the PI3K signaling pathway, and the expressions of proliferation markers (PCNA and MKI67) and the anti-apoptotic gene BCL2 were significantly increased by p65 and FGFR1. Furthermore, both p65 and FGFR1 were observed to promote cell proliferation and inhibit the cell apoptosis of GCs, and p65 was confirmed to bind at the -348/-338 region of FGFR1 to positively regulate its transcription. Moreover, p65 was further found to enhance the pro-proliferation and anti-apoptotic effects of FGFR1. Taken together, p65 may target the -348/-338 region of FGFR1, promote the transcription of FGFR1, and enhance the pro-proliferation effect and anti-apoptotic effect of FGFR1 to facilitate the growth of follicles. This study will provide useful information for further investigations on the p65-mediated-FGFR1 signaling pathway during folliculogenesis in mammals.
Insights
The transcription factor p65 targets the FGFR1 gene, promoting ovarian granulosa cell survival and follicular development. This discovery enhances understanding of the p65-FGFR1 signaling pathway in mammalian folliculogenesis.
Area of Science:
- Reproductive Biology
- Cellular and Molecular Biology
- Genetics and Genomics
Background:
- Abnormal apoptosis of ovarian granulosa cells (GCs) leads to impaired follicular development and reproductive dysfunction in female mammals.
- The PI3K signaling pathway, involving FGFR1 and the NF-κB p65 subunit, is implicated in GC proliferation and apoptosis.
- The regulatory relationship between p65 and FGFR1 transcription, and their combined effects on GC survival and follicular development, remain largely unelucidated.
Purpose of the Study:
- To investigate whether the NF-κB p65 subunit regulates the transcription of the FGFR1 gene.
- To elucidate the biological effects of p65 and FGFR1 on granulosa cell survival and follicular development.
- To explore the role of the p65-FGFR1 signaling pathway in mammalian folliculogenesis.
Main Methods:
- Expression analysis of p65 and FGFR1 in porcine follicles and GCs at different developmental stages.
- Investigation of the activation of the PI3K signaling pathway by p65 and FGFR1.
- Assessment of proliferation markers (PCNA, MKI67) and anti-apoptotic gene (BCL2) expression.
- Chromatin immunoprecipitation assays to determine p65 binding sites on the FGFR1 promoter.
- Functional assays to evaluate the impact of p65 and FGFR1 on GC proliferation and apoptosis.
Main Results:
- p65 and FGFR1 were exclusively expressed in porcine GCs, with levels increasing from small to large follicles.
- Both p65 and FGFR1 activated the PI3K pathway, upregulating proliferation markers (PCNA, MKI67) and the anti-apoptotic gene BCL2.
- p65 directly binds to the -348/-338 region of the FGFR1 promoter, positively regulating its transcription and enhancing its pro-proliferative and anti-apoptotic effects.
Conclusions:
- The NF-κB p65 subunit targets the FGFR1 gene promoter, enhancing FGFR1 transcription and its pro-survival effects on granulosa cells.
- The p65-FGFR1 signaling axis plays a crucial role in promoting GC proliferation and inhibiting apoptosis, thereby facilitating follicular development.
- This study provides critical insights into the molecular mechanisms governing folliculogenesis and identifies a potential therapeutic target for reproductive dysfunction.
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