Mechanically activated ion channel PIEZO1 is required for lymphatic valve formation.
Mechanically activated ion channel PIEZO1 is required for lymphatic valve formation.
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DOI：
10.1073/pnas.1817070115
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发表时间：
2018-12-11
影响因子：
11.1
通讯作者：
Patapoutian A
中科院分区：
文献类型：
--
作者：
Nonomura K;Lukacs V;Sweet DT;Goddard LM;Kanie A;Whitwam T;Ranade SS;Fujimori T;Kahn ML;Patapoutian A
PIEZO蛋白是机械激活的阳离子通道。最近，在家族性淋巴水肿患者中发现了人类PIEZO1的功能丧失突变，这表明PIEZO1在淋巴系统中发挥着重要作用。在本文中，我们利用内皮细胞中缺失PIEZO1的小鼠模型，证明了该离子通道对于淋巴管瓣膜的形成至关重要，而淋巴管瓣膜是体内淋巴正常循环的关键结构。PIEZO1在瓣膜形成中的作用，为理解PIEZO1变异如何导致患者淋巴功能障碍提供了机制上的见解。这项研究还拓展了PIEZO蛋白的作用范畴，使其不仅仅局限于急性信号分子（如触觉感知），同时也凸显了这些离子通道在发育过程中控制形态/结构特化方面的重要性。
PIEZO1是一种阳离子通道，可被诸如流体剪切应力或膜拉伸等机械力激活。患者中PIEZO1功能丧失突变与先天性淋巴水肿伴胸腔积液相关。然而，目前PIEZO1功能与淋巴系统发育或功能之间的机制联系尚不清楚。在此，我们分析了两种内皮细胞中缺失PIEZO1的小鼠品系（通过Tie2Cre或Lyve1Cre实现），发现它们出现胸腔积液并在出生后死亡。引人注目的是，这些小鼠的淋巴管瓣膜数量显著减少。淋巴管瓣膜对于确保淋巴的正常循环至关重要。机械力已被认为与淋巴管生成和瓣膜形成有关，但所涉及的机械感受器的身份尚不明确。已知淋巴管瓣膜发育所需的转录因子FOXC2和NFATc1在Tie2Cre;Piezo1cKO小鼠中的表达看似正常。然而，在Tie2Cre;Piezo1cKO小鼠中，与集体细胞迁移、肌动蛋白聚合以及细胞间连接重塑相关的瓣膜小叶突出过程受到了损害。与这些遗传学发现一致的是，在培养的淋巴管内皮细胞中，Yoda1对PIEZO1的激活诱导了肌动球蛋白和VE - 钙黏蛋白阳性细胞间黏附位点的主动重塑。我们的分析提供了证据，表明机械激活的离子通道PIEZO1是淋巴管瓣膜形成的关键调节因子。
PIEZOs are mechanically activated cation channels. Recently, loss-of-function mutations of human PIEZO1 were found among patients with familial lymphedema, suggesting a requirement of PIEZO1 in the lymphatic system. In this paper, utilizing mouse models lacking PIEZO1 in endothelial cells, we show that this ion channel is required for the formation of lymphatic valves, a key structure for proper circulation of lymph in the body. The requirement of PIEZO1 in valve formation provides mechanistic insight on how PIEZO1 variants cause lymphatic dysfunction in patients. This study also extends the relevance of PIEZOs beyond acute signaling molecules (e.g., touch sensation) and highlights the importance of these ion channels in controlling morphological/structural specification during development. PIEZO1 is a cation channel that is activated by mechanical forces such as fluid shear stress or membrane stretch. PIEZO1 loss-of-function mutations in patients are associated with congenital lymphedema with pleural effusion. However, the mechanistic link between PIEZO1 function and the development or function of the lymphatic system is currently unknown. Here, we analyzed two mouse lines lacking PIEZO1 in endothelial cells (via Tie2Cre or Lyve1Cre) and found that they exhibited pleural effusion and died postnatally. Strikingly, the number of lymphatic valves was dramatically reduced in these mice. Lymphatic valves are essential for ensuring proper circulation of lymph. Mechanical forces have been implicated in the development of lymphatic vasculature and valve formation, but the identity of mechanosensors involved is unknown. Expression of FOXC2 and NFATc1, transcription factors known to be required for lymphatic valve development, appeared normal in Tie2Cre;Piezo1cKO mice. However, the process of protrusion in the valve leaflets, which is associated with collective cell migration, actin polymerization, and remodeling of cell–cell junctions, was impaired in Tie2Cre;Piezo1cKO mice. Consistent with these genetic findings, activation of PIEZO1 by Yoda1 in cultured lymphatic endothelial cells induced active remodeling of actomyosin and VE-cadherin+ cell–cell adhesion sites. Our analysis provides evidence that mechanically activated ion channel PIEZO1 is a key regulator of lymphatic valve formation.
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压电2感应气道拉伸并介导肺通胀引起的呼吸暂停。
影响因子：
64.8
作者：
Nonomura K;Woo SH;Chang RB;Gillich A;Qiu Z;Francisco AG;Ranade SS;Liberles SD;Patapoutian A
通讯作者：
Patapoutian A
影响因子：
25
作者：
Madisen L;Zwingman TA;Sunkin SM;Oh SW;Zariwala HA;Gu H;Ng LL;Palmiter RD;Hawrylycz MJ;Jones AR;Lein ES;Zeng H
通讯作者：
Zeng H
DOI：
10.1161/atvbaha.117.309818
发表时间：
2017-09-01
影响因子：
8.7
作者：
Pujol, Francoise;Hodgson, Tina;Tatin, Florence
通讯作者：
Tatin, Florence
影响因子：
3
作者：
Glogowska E;Gallagher PG
通讯作者：
Gallagher PG
影响因子：
64.8
作者：
Ranade, Sanjeev S.;Woo, Seung-Hyun;Dubin, Adrienne E.;Moshourab, Rabih A.;Wetzel, Christiane;Petrus, Matt;Mathur, Jayanti;Begay, Valerie;Coste, Bertrand;Mainquist, James;Wilson, A. J.;Francisco, Allain G.;Reddy, Kritika;Qiu, Zhaozhu;Wood, John N.;Lewin, Gary R.;Patapoutian, Ardem
通讯作者：
Patapoutian, Ardem