Integrin-alpha9 is required for fibronectin matrix assembly during lymphatic valve morphogenesis.
Integrin-alpha9 is required for fibronectin matrix assembly during lymphatic valve morphogenesis.
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DOI：
10.1016/j.devcel.2009.06.017
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发表时间：
2009-08
影响因子：
11.8
通讯作者：
Makinen, Taija
中科院分区：
文献类型：
--
作者：
Bazigou, Eleni;Xie, Sherry;Chen, Chun;Weston, Anne;Miura, Naoyuki;Sorokin, Lydia;Adams, Ralf;Muro, Andres F.;Sheppard, Dean;Makinen, Taija
淋巴管瓣功能障碍是人类水肿的基础，但对淋巴管瓣形态发生的过程知之甚少。在这里，我们表明，在胚胎发育过程中，淋巴瓣小叶的形成是通过上调整合素-α9的表达及其配体纤连蛋白-EIIIA（FN-EIIIA）在细胞外基质中的沉积而启动的。在小鼠胚胎中，内皮细胞特异性缺失Itga 9（编码整合素-α9）导致发育不全的瓣叶，其特征在于紊乱的FN基质、短尖和逆行淋巴流。在缺乏FN的EIIIA结构域的小鼠中观察到类似的形态和功能缺陷。从机制上讲，我们证明了在原代人淋巴管内皮细胞中，整合素-α9-EIIIA相互作用直接调节FN原纤维组装，这对瓣膜小叶细胞外基质核心的形成至关重要。我们的研究结果揭示了整合素-α9信号在淋巴瓣形态发生中的重要作用，并暗示它是瓣膜缺陷引起原发性水肿的候选基因。
Dysfunction of lymphatic valves underlies human lymphedema, yet the process of valve morphogenesis is poorly understood. Here, we show that during embryogenesis lymphatic valve leaflet formation is initiated by upregulation of integrin-α9 expression and deposition of its ligand, fibronectin-EIIIA (FN-EIIIA), in the extracellular matrix. Endothelial cell specific deletion of Itga9 (encoding integrin-α9) in mouse embryos results in the development of rudimentary valve leaflets, characterized by disorganized FN matrix, short cusps and retrograde lymphatic flow. Similar morphological and functional defects are observed in mice lacking the EIIIA domain of FN. Mechanistically, we demonstrate that in primary human lymphatic endothelial cells the integrin-α9-EIIIA interaction directly regulates FN fibril assembly, which is essential for the formation of the extracellular matrix core of valve leaflets. Our findings reveal an important role for integrin-α9 signaling during lymphatic valve morphogenesis and implicate it as a candidate gene for primary lymphedema caused by valve defects.
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影响因子：
10.4
作者：
Hynes, R. O.
通讯作者：
Hynes, R. O.
影响因子：
5.3
作者：
Huang, XZ;Wu, JF;Sheppard, D
通讯作者：
Sheppard, D
影响因子：
7.5
作者：
Kadler KE;Hill A;Canty-Laird EG
通讯作者：
Canty-Laird EG
影响因子：
7.8
作者：
Fogerty, F J;Akiyama, S K;Yamada, K M;Mosher, D F
通讯作者：
Mosher, D F
影响因子：
3.5
作者：
Ferrell, RE;Levinson, KL;Finegold, DN
通讯作者：
Finegold, DN