Ayadi A, Zheng H, Sobieszczuk P, Buchwalter G, Moerman P, Alitalo K, Wasylyk B
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, 1 Rue Laurent Fries, BP 163, 67404 Illkirch cedex, France.
EMBO J. 2001 Sep 17;20(18):5139-52. doi: 10.1093/emboj/20.18.5139.
The ternary complex factors (TCFs) Net, Elk-1 and Sap-1 regulate immediate early genes through serum response elements (SREs) in vitro, but, surprisingly, their in vivo roles are unknown. Net is a repressor that is expressed in sites of vasculogenesis during mouse development. We have made gene-targeted mice that express a hypomorphic mutant of Net, Net delta, which lacks the Ets DNA-binding domain. Strikingly, homozygous mutant mice develop a vascular defect and up-regulate an immediate early gene implicated in vascular disease, egr-1. They die after birth due to respiratory failure, resulting from the accumulation of chyle in the thoracic cage (chylothorax). The mice have dilated lymphatic vessels (lymphangiectasis) as early as E16.5. Interestingly, they express more egr-1 in heart and pulmonary arteries at E18.5. Net negatively regulates the egr-1 promoter and binds specifically to SRE-5. Egr-1 has been associated with pathologies involving vascular stenosis (e.g. atherosclerosis), and here egr-1 dysfunction could possibly be associated with obstructions that ultimately affect the lymphatics. These results show that Net is involved in vascular biology and egr-1 regulation in vivo.
三元复合因子（TCFs）Net、Elk-1和Sap-1在体外通过血清反应元件（SREs）调节即刻早期基因，但令人惊讶的是，它们在体内的作用尚不清楚。Net是一种阻遏物，在小鼠发育过程中的血管生成部位表达。我们制备了基因靶向小鼠，其表达Net的低表达突变体Net delta，该突变体缺乏Ets DNA结合结构域。引人注目的是，纯合突变小鼠出现血管缺陷，并上调一种与血管疾病相关的即刻早期基因egr-1。它们出生后因胸腔内乳糜积聚（乳糜胸）导致呼吸衰竭而死亡。这些小鼠早在胚胎第16.5天就出现淋巴管扩张（淋巴管扩张症）。有趣的是，它们在胚胎第18.5天时在心脏和肺动脉中表达更多的egr-1。Net负向调节egr-1启动子，并特异性结合SRE-5。Egr-1与涉及血管狭窄（如动脉粥样硬化）的病理过程有关，在这里egr-1功能障碍可能与最终影响淋巴管的阻塞有关。这些结果表明Net在体内参与血管生物学和egr-1调节。
