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SMAD4 activates Wnt signaling pathway to inhibit granulosa cell apoptosis

Xing Du1, Qiqi Li1, Liu Yang1

  • 1College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, 210095, China.

Cell Death & Disease
|May 17, 2020
PubMed

Insights

SMAD4, a TGF-β pathway effector, induces FZD4, a Wnt pathway receptor, creating a novel communication route in granulosa cells. This SMAD4-FZD4 axis regulates cell apoptosis and offers potential therapeutic targets for reproductive diseases.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Reproductive Biology

Background:

  • TGF-β and Wnt signaling pathways are crucial for coordinating cell functions.
  • Interplay between these pathways is vital in various cell types and tissues.
  • Granulosa cells (GCs) play a key role in ovarian function and follicular development.

Purpose of the Study:

  • To investigate the communication between TGF-β and Wnt signaling pathways in granulosa cells.
  • To identify novel regulatory mechanisms controlling granulosa cell apoptosis.
  • To explore potential therapeutic targets for reproductive diseases.

Main Methods:

  • Investigated the role of SMAD4 in regulating FZD4 expression in GCs.
  • Analyzed the direct transcriptional regulation of FZD4 by SMAD4.
  • Identified the indirect regulatory mechanism involving lncRNA SDNOR and miR-29c.

Main Results:

  • SMAD4 directly induces FZD4 transcription and activates Wnt signaling in GCs.
  • SMAD4 promotes GC apoptosis via the FZD4-dependent pathway.
  • A novel regulatory axis, SMAD4-FZD4, was identified, involving direct binding and lncRNA-mediated mechanisms.
  • SMAD4 induces the lncRNA SDNOR, which sponges miR-29c, preventing degradation of FZD4 mRNA.

Conclusions:

  • A novel crosstalk between TGF-β and Wnt pathways via the SMAD4-FZD4 axis in GCs was discovered.
  • This pathway significantly impacts GC apoptosis and follicular atresia.
  • miR-29c and lnc-SDNOR represent potential therapeutic targets for reproductive disorders and fertility enhancement.

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