Cdk5 controls lymphatic vessel development and function by phosphorylation of Foxc2
Cdk5 controls lymphatic vessel development and function by phosphorylation of Foxc2
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DOI：
10.1038/ncomms8274
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发表时间：
2015-06-01
影响因子：
16.6
通讯作者：
Zahler, Stefan
中科院分区：
文献类型：
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作者：
Liebl, Johanna;Zhang, Siwei;Zahler, Stefan
淋巴系统维持组织液平衡，淋巴管和瓣膜功能障碍导致人类淋巴水肿综合征。然而，我们对淋巴管发育的分子机制的了解仍然有限。在这里，我们证明了细胞周期蛋白依赖性激酶5(CDK5)是淋巴管发育的重要调节因子。内皮特异性CDK5基因敲除导致先天性淋巴功能障碍和淋巴水肿，原因是淋巴管构型和瓣膜形成缺陷。我们发现转录因子FOXC2是淋巴管系统中CDK5的关键底物，机械地将CDK5与淋巴管发育和瓣膜形态发生联系起来。总之，我们的发现表明，CDK5-FOXC2相互作用代表了淋巴管发育的关键调节因子和淋巴管重塑的转录网络。
The lymphatic system maintains tissue fluid balance, and dysfunction of lymphatic vessels and valves causes human lymphedema syndromes. Yet, our knowledge of the molecular mechanisms underlying lymphatic vessel development is still limited. Here, we show that cyclin-dependent kinase 5 (Cdk5) is an essential regulator of lymphatic vessel development. Endothelial-specific Cdk5 knockdown causes congenital lymphatic dysfunction and lymphedema due to defective lymphatic vessel patterning and valve formation. We identify the transcription factor Foxc2 as a key substrate of Cdk5 in the lymphatic vasculature, mechanistically linking Cdk5 to lymphatic development and valve morphogenesis. Collectively, our findings show that Cdk5-Foxc2 interaction represents a critical regulator of lymphatic vessel development and the transcriptional network underlying lymphatic vascular remodeling.