Mechanotransduction, PROX1, and FOXC2 Cooperate to Control Connexin37 and Calcineurin during Lymphatic-Valve Formation
Mechanotransduction, PROX1, and FOXC2 Cooperate to Control Connexin37 and Calcineurin during Lymphatic-Valve Formation
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DOI：
10.1016/j.devcel.2011.12.020
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发表时间：
2012-02-14
影响因子：
11.8
通讯作者：
Petrova, Tatiana V.
中科院分区：
文献类型：
--
作者：
Sabine, Amelie;Agalarov, Yan;Petrova, Tatiana V.
淋巴阀是有效淋巴运输的必要条件，但其机制。早期淋巴瓣膜的形态发生和生物力学力的作用尚不清楚。我们发现转录因子PROX1和FOXC2从瓣膜形成开始就高度表达，介导体外淋巴瓣膜形成细胞的分离和细胞对剪切应力的机械感觉反应。在机制上，PROX1、FOXC2和flow协调控制间隙连接蛋白connexin37的表达和钙调神经磷酸酶/NFAT信号的激活。Connexin37和钙调磷酸酶是发育过程中淋巴阀区域的组装和划分及其产后维护所必需的。我们提出了一个模型，在该模型中，转录因子的区域增加水平/激活状态与机械转导合作，诱导离散的细胞信号传导模式和形态发生事件，如淋巴阀的形成。我们的研究结果还提供了内皮细胞身份在血管机械转导调节中的作用的分子见解。
Lymphatic valves are essential for efficient lymphatic transport, but the mechanisms. of early lymphatic-valve morphogenesis and the role of biomechanical forces are not well understood. We found that the transcription factors PROX1 and FOXC2, highly expressed from the onset of valve formation, mediate segregation of lymphatic-valve-forming cells and cell mechanosensory responses to shear stress in vitro. Mechanistically, PROX1, FOXC2, and flow coordinately control expression of the gap junction protein connexin37 and activation of calcineurin/NFAT signaling. Connexin37 and calcineurin are required for the assembly and delimitation of lymphatic valve territory during development and for its postnatal maintenance. We propose a model in which regionally increased levels/activation states of transcription factors cooperate with mechanotransduction to induce a discrete cell-signaling pattern and morphogenetic event, such as formation of lymphatic valves. Our results also provide molecular insights into the role of endothelial cell identity in the regulation of vascular mechanotransduction.