A novel positive feedback regulatory loop, TGF-β1/SMAD4/miR-184, controls the follicular development in sows
4 affiliations
- 1College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu 210095, China
- 2College of Animal Husbandry and Veterinary Medicine, Jiangsu Vocational College of Agriculture and Forestry, Zhenjiang, Jiangsu 212400, China
- 3National Experimental Teaching Demonstration Center for Animal Science, Nanjing Agricultural University, Nanjing, Jiangsu 210095, China
- 4College of Food Science and Engineering, Shandong Agricultural University, Taian, Shandong 271018, China
Abstract
TGF-β1, the core ligand of the transforming growth factor β (TGF-β) signaling pathway, is crucial for follicular development and female fertility. However, it remains unclear whether microRNAs (miRNAs), an important class of epigenetic regulators, mediate the anti-atretic effect of TGF-β1. Here, joint transcriptomic analysis demonstrated that miR-184, an anti-atretic miRNA, was significantly elevated by TGF-β1 in sow granulosa cells (GCs). Quantitative detection, correlation analysis, luciferase reporter assays, and chromatin immunoprecipitation confirmed that TGF-β1 induces miR-184 transcription in a SMAD4-dependent manner, with SMAD4 acting as a transcriptional activator that directly binds to the miR-184 promoter under TGF-β1 stimulation. RNA-seq and bioinformatics analysis revealed that the target genes of miR-184 are enriched in the TGF-β pathway, with TGF-β1 being feedback-induced by miR-184. In vivo and in vitro mechanistic analyses revealed that miR-184, a small-activating RNA (saRNA), activates TGF-β1 transcription by binding to its promoter and forming an RNA-induced transcriptional activation complex with AGO2, CTR9, DHX9, and RNA polymerase II. Consequently, a novel positive feedback loop (TGF-β1/SMAD4/miR-184) was identified. In vitro GC and follicle culture systems validated the anti-apoptotic/atretic functions of this loop. Moreover, comparative analyses showed that the levels of TGF-β1 and miR-184 in the follicles of high-fertility sows were significantly higher than those in low-fertility sows. Our findings highlight the critical role of the interaction between TGF-β1 and miR-184 in inhibiting GC apoptosis and follicular atresia, providing potential targets for improving follicular development and sow fertility.
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BibTeX
@article{li2026novel,
title = {{A novel positive feedback regulatory loop, TGF-β1/SMAD4/miR-184, controls the follicular development in sows}},
author = {Qi-Qi Li and Hao-Yang Lu and Cheng Luo and Zhen-Nan Guo and Xiao-Li Shi and Bao-Sen Shan and Shan-Feng Wang and Qi-Fa Li and Xing Du},
journal = {Zoological Research},
year = {2026},
month = sep,
doi = {10.24272/j.issn.2095-8137.2025.578},
url = {https://doi.org/10.24272/j.issn.2095-8137.2025.578},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - A novel positive feedback regulatory loop, TGF-β1/SMAD4/miR-184, controls the follicular development in sows
AU - Qi-Qi Li
AU - Hao-Yang Lu
AU - Cheng Luo
AU - Zhen-Nan Guo
AU - Xiao-Li Shi
AU - Bao-Sen Shan
AU - Shan-Feng Wang
AU - Qi-Fa Li
AU - Xing Du
PY - 2026
DA - 2026/09/18
JO - Zoological Research
DO - 10.24272/j.issn.2095-8137.2025.578
UR - https://doi.org/10.24272/j.issn.2095-8137.2025.578
AB - TGF-β1, the core ligand of the transforming growth factor β (TGF-β) signaling pathway, is crucial for follicular development and female fertility. However, it remains unclear whether microRNAs (miRNAs), an important class of epigenetic regulators, mediate the anti-atretic effect of TGF-β1. Here, joint transcriptomic analysis demonstrated that miR-184, an anti-atretic miRNA, was significantly elevated by TGF-β1 in sow granulosa cells (GCs). Quantitative detection, correlation analysis, luciferase reporter assays, and chromatin immunoprecipitation confirmed that TGF-β1 induces miR-184 transcription in a SMAD4-dependent manner, with SMAD4 acting as a transcriptional activator that directly binds to the miR-184 promoter under TGF-β1 stimulation. RNA-seq and bioinformatics analysis revealed that the target genes of miR-184 are enriched in the TGF-β pathway, with TGF-β1 being feedback-induced by miR-184. In vivo and in vitro mechanistic analyses revealed that miR-184, a small-activating RNA (saRNA), activates TGF-β1 transcription by binding to its promoter and forming an RNA-induced transcriptional activation complex with AGO2, CTR9, DHX9, and RNA polymerase II. Consequently, a novel positive feedback loop (TGF-β1/SMAD4/miR-184) was identified. In vitro GC and follicle culture systems validated the anti-apoptotic/atretic functions of this loop. Moreover, comparative analyses showed that the levels of TGF-β1 and miR-184 in the follicles of high-fertility sows were significantly higher than those in low-fertility sows. Our findings highlight the critical role of the interaction between TGF-β1 and miR-184 in inhibiting GC apoptosis and follicular atresia, providing potential targets for improving follicular development and sow fertility.
SN - 2095-8137
ER -