SMAD4 activates Wnt signaling pathway to inhibit granulosa cell apoptosis
SMAD4 activates Wnt signaling pathway to inhibit granulosa cell apoptosis
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SMAD4激活Wnt信号通路抑制颗粒细胞凋亡
DOI：
10.1038/s41419-020-2578-x
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发表时间：
2020-05-15
影响因子：
9
通讯作者：
Li, Qifa
中科院分区：
文献类型：
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作者：
Du, Xing;Li, Qiqi;Li, Qifa
TGF-β和WNT信号通路在许多细胞类型和组织中都相互关联，并控制了在协调中的细胞功能。在这里，我们报告说，TGF-β信号通路的下游效应子Smad4诱导FZD4（Wnt信号通路的受体FZD4）在颗粒细胞中这两种途径之间建立了新的通信途径（GCS）。我们发现SMAD4是FZD4的强诱导剂，不仅启动FZD4转录，而且还激活FZD4依赖性Wnt信号传导和GC凋亡。此外，我们确定了SMAD4在GC中促进FZD4表达的直接和间接机制。首先，SMAD4充当转录因子，直接与FZD4启动子区域结合以增加其转录活性。其次，SMAD4促进了SDNOR的生产，SDNOR是一种新型的lncRNA，充当miR-29c的海绵，这提供了另一个均值，可以阻止miR-29c从退化的FZD4 mRNA中。总体而言，我们的发现不仅揭示了TGF-beta和Wnt信号通路之间的串扰新通道SMAD4-FZD4轴，而且还提供了有关GC凋亡和卵泡闭锁的调节网络的新见解。这些RNA分子，例如miR-29c和LNC-SDNOR，代表了治疗生殖疾病的潜在靶标和女性生育能力的改善。
The TGF-beta and Wnt signaling pathways are interrelated in many cell types and tissues, and control cell functions in coordination. Here, we report that SMAD4, a downstream effector of the TGF-beta signaling pathway, induces FZD4, a receptor of the Wnt signaling pathway, establishing a novel route of communication between these two pathways in granulosa cells (GCs). We found that SMAD4 is a strong inducer of FZD4, not only initiating FZD4 transcription but also activating FZD4-dependent Wnt signaling and GC apoptosis. Furthermore, we identified the direct and indirect mechanisms by which SMAD4 promotes expression of FZD4 in GCs. First, SMAD4 functions as a transcription factor to directly bind to the FZD4 promoter region to increase its transcriptional activity. Second, SMAD4 promotes production of SDNOR, a novel lncRNA that acts as a sponge for miR-29c, providing another mean to block miR-29c from degenerating FZD4 mRNA. Overall, our findings not only reveal a new channel of crosstalk between the TGF-beta and Wnt signaling pathways, SMAD4-FZD4 axis, but also provide new insights into the regulatory network of GC apoptosis and follicular atresia. These RNA molecules, such as miR-29c and lnc-SDNOR, represent potential targets for treatment of reproductive diseases and improvement of female fertility.