TGF‐β/SMAD4 signaling pathway activates the HAS2–HA system to regulate granulosa cell state. Issue 3 (6th September 2019)

• Record Type: Journal Article
• Authors: Li, Xinyu; Du, Xing; Yao, Wang; Pan, Zengxiang; Li, Qifa
• Is Part Of: Journal of cellular physiology. Volume 235:Issue 3(2020:Mar.)
• Page Start: 2260
• Page End: 2272
• Publication Date: 2019-09-06
• Subjects: granulosa cell state -- HAS2–HA system -- SMAD4 -- TGF‐β/SMAD4 signaling pathway; Physiology -- Periodicals; Cell physiology -- Periodicals; 571.6
• DOI: 10.1002/jcp.29134
• Languages: English
• ISSNs: 0021-9541

Abstract

Abstract: Both TGF‐β/SMAD4 signaling pathway and HAS2–HA system have been shown to control granulosa cell (GC) state in mammalian ovary. However, the regulatory relationship between TGF‐β/SMAD4 signaling pathway and HA system in GCs is not well known. Here, we report that the TGF‐β/SMAD4 signaling pathway activates the HAS2–HA system by binding directly to the HAS2 promoter, ultimately controlling the GC state via the CD44–Caspase3 axis. SMAD4‐induced HAS2 expression, HAS2‐driven HA secretion, and HAS2‐mediated GC state (proliferation and apoptosis) by interacting directly with the promoter region of the HAS2 gene. The CD44–Caspase3 axis, located downstream of the HAS2–HA system, was also activated by SMAD4 and the TGF‐β/SMAD4 signaling pathway. However, there was no feedback regulation of the TGF‐β/SMAD4 signaling pathway by the HAS2–HA system in GCs. In addition, we found that miRNA‐26b attenuated HAS2 expression via SMAD4‐dependent and ‐independent mechanisms. Our findings provide compelling evidence that HAS2 is a direct transcriptional target of SMAD4. They also reveal a novel mechanism by which the TGF‐β/SMAD4 signaling pathway controls the GC state and alters the structural components of GCs in porcine ovaries. Abstract : SMAD4 controls HAS2–HA system and its role in granulosa cell (GC) state by interacting directly with HAS2 promoter. TGF‐β/SMAD4 signaling pathway was not feedback regulated by the HAS2–HA system in GCs. miRNA‐26b attenuated HAS2 expression via SMAD4‐dependent and ‐independent mechanisms.