Mmp15 is a direct target of Snai1 during endothelial to mesenchymal transformation and endocardial cushion development.
Mmp15 is a direct target of Snai1 during endothelial to mesenchymal transformation and endocardial cushion development.
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DOI：
10.1016/j.ydbio.2011.08.022
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发表时间：
2011-11-15
影响因子：
2.7
通讯作者：
Lincoln J
中科院分区：
文献类型：
--
作者：
Tao G;Levay AK;Gridley T;Lincoln J
心脏瓣膜起源于胚胎发育过程中内皮细胞向间质转化形成的心内膜垫(EC)。锌指转录因子Snai1此前已被报道在器官发生过程中对EMT起重要作用，但它在瓣膜早期发育中的作用尚未被直接研究。在本研究中，我们发现在EC发育过程中，Snai1在内皮细胞和新转化的间质细胞中高表达。靶向Snai1基因敲除的小鼠在E10.5出现低细胞内皮细胞，与间充质细胞标记物表达减少和基质金属蛋白酶(MMP15)家族成员MMP15下调有关。Snai1在房室管I型胶原凝胶移植体内的过表达研究表明，Snai1足以促进MMP15的表达、细胞转化以及间充质细胞的迁移和侵袭。然而，用催化活性形式的MMP15处理促进了细胞的运动，而不是转化。此外，我们发现Snai1介导的细胞迁移需要基质金属蛋白酶的活性，而caMMP15治疗挽救了Snai1基因敲除后在小鼠内皮细胞中观察到的减弱的迁移缺陷。综上所述，这项研究的结果揭示了以前未被认可的Snai1在EC发育过程中直接调节MMPs的机制。
Cardiac valves originate from endocardial cushions (EC) formed by endothelial-to-mesenchymal transformation (EMT) during embryogenesis. The zinc-finger transcription factor Snai1 has previously been reported to be important for EMT during organogenesis, yet its role in early valve development has not been directly examined. In this study we show that Snai1 is highly expressed in endothelial, and newly transformed mesenchyme cells during EC development. Mice with targeted snai1 knockdown display hypocellular ECs at E10.5 associated with decreased expression of mesenchyme cell markers and downregulation of the matrix metalloproteinase (mmp) family member, mmp15. Snai1 overexpression studies in atrioventricular canal collagen I gel explants indicate that Snai1 is sufficient to promote mmp15 expression, cell transformation, and mesenchymal cell migration and invasion. However, treatment with the catalytically active form of MMP15 promotes cell motility, and not transformation. Further, we show that Snai1-mediated cell migration requires MMP activity, and caMMP15 treatment rescues attenuated migration defects observed in murine ECs following snai1 knockdown. Together, findings from this study reveal previously unappreciated mechanisms of Snai1 for the direct regulation of MMPs during EC development.
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影响因子：
2.5
作者：
Lincoln, J;Alfieri, CM;Yutzey, KE
通讯作者：
Yutzey, KE
影响因子：
2.7
作者：
BERNANKE, DH;MARKWALD, RR
通讯作者：
MARKWALD, RR
影响因子：
5.3
作者：
Carver, EA;Jiang, RL;Gridley, T
通讯作者：
Gridley, T
影响因子：
4
作者：
Ikenouchi, J;Matsuda, M;Tsukita, S
通讯作者：
Tsukita, S
影响因子：
4
作者：
Joseph, Mathew J.;Dangi-Garimella, Surabbi;Munshi, Hidayatullah G.
通讯作者：
Munshi, Hidayatullah G.