Department of Genetics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Genes Dev. 2011 Oct 15;25(20):2187-97. doi: 10.1101/gad.16974811.
Arteries, veins, and lymphatic vessels are functionally linked, and their physical interaction is tightly regulated. The lymphatic vessels communicate with the blood vessels only at the junction of the jugular and subclavian veins. Here, we characterize the embryonic lymphovenous valves controlling this vital communication and show that they are formed by the intercalation of lymphatic endothelial cells (LECs) with a subpopulation of venous endothelial cells (ECs) at the junction of the jugular and subclavian veins. We found that unlike LEC progenitors, which move out from the veins and differentiate into mature LECs, these Prox1-expressing ECs remain in the veins and do not acquire LEC features. We demonstrate that the development of this Prox1-expressing venous EC population, and therefore of lymphovenous valves, requires two functional copies of Prox1, as the valves are absent in Prox1 heterozygous mice. We show that this is due to a defect in the maintenance of Prox1 expression in venous ECs and LEC progenitors promoted by a reduction in Coup-TFII/Prox1 complex formation. This is the first report describing the molecular mechanism controlling lymphovenous communication.
动脉、静脉和淋巴管在功能上是相连的，它们的物理相互作用受到严格的调节。淋巴管仅在颈静脉和锁骨下静脉的交界处与血管相通。在这里，我们描述了控制这种重要通讯的胚胎性淋静脉瓣膜，并表明它们是由淋巴管内皮细胞（LEC）与颈静脉和锁骨下静脉交界处的一部分静脉内皮细胞（EC）插入形成的。我们发现，与从静脉中迁移并分化为成熟 LEC 的 LEC 前体不同，这些表达 Prox1 的 EC 留在静脉中，并不具有 LEC 特征。我们证明，这种表达 Prox1 的静脉 EC 群体的发育，以及因此淋静脉瓣膜的发育，需要两个功能性的 Prox1 拷贝，因为在 Prox1 杂合子小鼠中瓣膜不存在。我们表明，这是由于 Coup-TFII/Prox1 复合物形成减少，导致静脉 EC 和 LEC 前体中 Prox1 表达的维持出现缺陷所致。这是第一个描述控制淋静脉通讯的分子机制的报告。
