ArticleCell death & disease2023
FHL2 deficiency impairs follicular development and fertility by attenuating EGF/EGFR/YAP signaling in ovarian granulosa cells.
Article in Cell death & disease, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 22 citations in OpenAlex.
- A Novel Role of DELTEX2 in Maintaining Genomic Stability of Granulosa Cells During Ovarian Aging.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2026Article
- YAP1 Is Associated with Cumulus Expansion-Related Factor Expression and Autophagy-Related Signaling in Yak Cumulus Cells.Animals : an open access journal from MDPI · 2026Article
- Construction of TF-lncRNA-miRNA-mRNA Regulatory Network Affecting Sow Reproduction Based on QTLs for Corpus Luteum Number.Animals : an open access journal from MDPI · 2026Article
- Integrated Network Toxicology and Metabolomics Reveal the Ovarian Toxicity Mechanisms of Chronic Carbofuran Exposure in Female Mice.International journal of molecular sciences · 2025Article
- Hypo-glycosylated FSH enhances the ovarian microenvironment for follicular development compared to fully glycosylated FSH.Cell communication and signaling : CCS · 2025Article
- Pituitary-derived Follicle stimulating hormone has greater follicle-stimulating bioactivity than recombinant Follicle stimulating hormone possibly due to glycoform variants†.Biology of reproduction · 2025Article
- MicroRNA (miRNA) in Plasma Small Extracellular Vesicles (sEV) as Potential Early Indicators of Dairy Cow Subfertility.Journal of extracellular biology · 2025Article
- Hyperandrogenism-mediated YAP activation drives ovarian inflammation and pyroptosis in PCOS: implications for follicular dysfunction.Journal of ovarian research · 2025Article
- Metabolomic Analysis Identifies Betaine as a Key Mediator ofInternational journal of molecular sciences · 2025Article
- Latitude-driven adaptive evolution of body length in diverse pig breeds across China.BMC biology · 2025Article
- LRRC4 Deficiency Drives Premature Ovarian Insufficiency by Disrupting Metabolic Homeostasis in Granulosa Cells.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Article
- Porcine granulosa cell transcriptomic analyses reveal the differential regulation of lncRNAs and mRNAs in response to all-trans retinoic acid in vitro.Animal bioscience · 2025Article
- Electroacupuncture enhances the mitophagy of granulosa cells in premature ovarian insufficiency model mice by inactivating the hippo-yes-associated protein/transcriptional co-activator with postsynaptic density protein, drosophila disc large tumor suppressor, and zonula occludens-1 protein binding motif pathway.Journal of traditional Chinese medicine = Chung i tsa chih ying wen pan · 2025Article
- Targeting programmed cell death with natural products: a potential therapeutic strategy for diminished ovarian reserve and fertility preservation.Frontiers in pharmacology · 2025Review
- Nicotinamide Mononucleotide Restores NADAntioxidants (Basel, Switzerland) · 2024Article
- miR-184, a downregulated ovary-elevated miRNA transcriptionally activated by SREBF2, exerts anti-apoptotic properties in ovarian granulosa cells through inducing SMAD3 expression.Cell death & disease · 2024Article
- Construction and Analysis of miRNA-mRNA Interaction Network in Ovarian Tissue of Wanxi White Geese Across Different Breeding Stages.Animals : an open access journal from MDPI · 2024Article
- ADPN Regulates Oxidative Stress-Induced Follicular Atresia in Geese by Modulating Granulosa Cell Apoptosis and Autophagy.International journal of molecular sciences · 2024Article
- Article
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Authors and funding
15 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Female subfertility is an increasing reproductive issue worldwide, which is partially related to abnormal ovarian follicular development. Granulosa cells (GCs), by providing the necessary physical support and microenvironment for follicular development, play critical roles in maintaining female fertility. We previously showed that ectopic expression of four and a half LIM domains 2 (FHL2) promoted ovarian granulosa cell tumor progression. However, its function in follicular development and fertility remains unknown. Here, we confirmed that FHL2 is highly expressed in human and mouse ovaries. FHL2 immunosignals were predominantly expressed in ovarian GCs. A Fhl2 knockout (KO) mouse model was generated to examine its roles in follicular development and fertility. Compared with wildtype, knockout of Fhl2 significantly decreased female litter size and offspring number. Furthermore, Fhl2 deficiency reduced ovarian size and impaired follicular development. RNA-sequencing analysis of GCs isolated from either KO or WT mice revealed that, Fhl2 deletion impaired multiple biological functions and signaling pathways, such as Ovarian Putative Early Atresia Granulosa Cell, ErbB, Hippo/YAP, etc. In vitro studies confirmed that FHL2 silencing suppressed GCs growth and EGF-induced GCs proliferation, while its overexpression promoted GC proliferation and decreased apoptosis. Mechanistic studies indicated that FHL2, via forming complexes with transcriptional factors AP-1 or NF-κB, regulated Egf and Egfr expression, respectively. Besides, FHL2 depletion decreased YAP1 expression, especially the active form of YAP1 (nuclear YAP1) in GCs of growing follicles. EGF, serving as an autocrine/paracrine factor, not only induced FHL2 expression and nuclear accumulation, but also stimulated YAP1 expression and activation. Collectively, our study suggests that FHL2 interacts with EGFR and Hippo/YAP signaling to regulate follicular development and maintain fertility. This study illuminates a novel mechanism for follicular development and a potential therapeutic target to address subfertility.
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