Hormone-Responsive BMP Signaling Expands Myoepithelial Cell Lineages and Prevents Alveolar Precocity in Mammary Gland.
Hormone-Responsive BMP Signaling Expands Myoepithelial Cell Lineages and Prevents Alveolar Precocity in Mammary Gland.
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激素响应性 BMP 信号传导可扩展肌上皮细胞谱系并预防乳腺肺泡早熟
DOI：
10.3389/fcell.2021.691050
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发表时间：
2021
影响因子：
5.5
通讯作者：
Yu Z
中科院分区：
文献类型：
--
作者：
Shao C;Lou P;Liu R;Bi X;Li G;Yang X;Sheng X;Xu J;Lv C;Yu Z
肌上皮细胞和管腔细胞在怀孕期间在乳腺中协同扩张，并且该过程精确地由乳腺癌相关信号通路控制。骨形态发生蛋白（BMP）信号通路在所有器官系统中起着至关重要的作用。然而，BMP信号在乳腺中的功能仍不清楚。在这里，我们发现BMPR 1a在怀孕时被乳腺癌诱导的Sp1上调。使用多西环素（Dox）诱导的BMPR 1a条件性敲除小鼠模型，我们证明了在肌上皮中BMPR 1a的损失导致肌上皮完整性受损，乳腺干细胞减少和妊娠期间过早的肺泡分化。机制上，BMPR 1a通过pSmad 1/5-Smad 4复合物调节肌上皮维持的两个关键调节因子p63和Slug的表达，从而在妊娠期间激活P-钙粘蛋白。此外，我们观察到肌上皮中BMPR 1a的缺失导致分泌蛋白Spp 1的上调，这可以解释腔层中过早的肺泡分化，这表明基底-腔旁分泌信号机制有缺陷。总的来说，这些发现确定了BMP信号在维持肌上皮细胞身份和抑制过早肺泡形成方面的新作用。
Myoepithelial and luminal cells synergistically expand in the mammary gland during pregnancy, and this process is precisely governed by hormone-related signaling pathways. The bone morphogenetic protein (BMP) signaling pathway is now known to play crucial roles in all organ systems. However, the functions of BMP signaling in the mammary gland remain unclear. Here, we found that BMPR1a is upregulated by hormone-induced Sp1 at pregnancy. Using a doxycycline (Dox)-inducible BMPR1a conditional knockout mouse model, we demonstrated that loss of BMPR1a in myoepithelium results in compromised myoepithelial integrity, reduced mammary stem cells and precocious alveolar differentiation during pregnancy. Mechanistically, BMPR1a regulates the expression of p63 and Slug, two key regulators of myoepithelial maintenance, through pSmad1/5-Smad4 complexes, and consequently activate P-cadherin during pregnancy. Furthermore, we observed that loss of BMPR1a in myoepithelium results in the upregulation of a secreted protein Spp1 that could account for the precocious alveolar differentiation in luminal layer, suggesting a defective basal-to-luminal paracrine signaling mechanism. Collectively, these findings identify a novel role of BMP signaling in maintaining the identity of myoepithelial cells and suppressing precocious alveolar formation.
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影响因子：
10.5
作者：
Cai C;Yu QC;Jiang W;Liu W;Song W;Yu H;Zhang L;Yang Y;Zeng YA
通讯作者：
Zeng YA
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21.3
作者：
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通讯作者：
Visvader, Jane E.
影响因子：
64.8
作者：
Asselin-Labat, Marie-Liesse;Vaillant, Francois;Visvader, Jane E.
通讯作者：
Visvader, Jane E.