Prox1 and COUP-TFII interactions regulate lymphatic endothelial cell differentiation

项目摘要 淋巴系统是一个复杂的血管和组织网络，它运输含有以下物质的淋巴液 蛋白质、大分子和渗出的细胞从周围组织回到循环中。流量的流动 淋巴进入淋巴管很大程度上是由局部间质压力的变化驱动的，间质压力向淋巴管发出信号 内皮细胞(LECs)通过将细丝锚定在周围的细胞外基质中。作为对.的回应 增加间质压力，锚定细丝拉动晶状体上皮细胞，扩大重叠的细胞-细胞连接，并 允许淋巴流入淋巴管。发育障碍可导致先天性淋巴管 畸形和恶性肿瘤，而出生后淋巴功能障碍可导致病理 淋巴积聚和慢性免疫和消化问题。尽管LEC在以下方面发挥了重要作用 淋巴系统发育和组织液稳态，指定和维持LEC的信号识别 都没有得到很好的描述。先前的研究表明，晶状体上皮细胞可从静脉内皮细胞分化而来 同源结构域转录因子Prox1是这一谱系转换过程的主要调节因子。 在胚胎发育期间，大静脉的静脉内皮细胞亚群表达Prox1并向外迁移 形成不发育的淋巴管。已知这些Prox1阳性细胞下调该基因的表达 与静脉内皮细胞相关的基因识别和上调基因表达特征与 LECs。然而，Prox1介导的LEC分化的确切机制尚不清楚。我们 此前研究表明，Prox1与静脉内皮细胞命运调节因子COUP-TFII具有物理相互作用。这 初步研究表明，除了促进静脉内皮细胞分化外，COUP-TFII还 与Prox1合作建立和维护LEC谱系，这是假设的基础 拟议的研究。静脉内皮细胞特性的关键分子调节因子在 淋巴发育中的重要作用引起了人们的极大兴趣，并突出了密切的组织发生关系 在两个血管系统之间。通过剖析Prox1和Coup-TFII之间的分子相互作用 在LEC的发育过程中，这项提议旨在阐明协调 内皮细胞分化与动静脉淋巴管发育的认识 和疾病。

PROJECT ABSTRACT The lymphatic system is a complex vascular and tissue network that transports the lymph fluid containing proteins, macromolecules, and extravasated cells from peripheral tissues back to the circulation. The flow of lymph into lymphatic vessels is largely driven by local changes in interstitial pressure, which signals to lymphatic endothelial cells (LECs) through anchoring filaments in the surrounding extra cellular matrix. In response to increased interstitial pressure, anchoring filaments pull LECs to widen the overlapping cell-cell junctions and allow the flow of lymph into lymphatic vessels. Perturbations in development can lead to congenital lymphatic malformations and malignancies, while disruptions in post-natal lymphatic function can lead to pathologic lymphatic fluid accumulation and chronic immune and digestive problems. Despite the essential role of LECs in lymphatic system development and tissue fluid homeostasis, the signals that specify and maintain LEC identify are not well described. Previous studies have shown that LECs differentiate from venous endothelial cells and that homeodomain transcription factor Prox1 serves as a master regulator of this lineage conversion process. During embryogenesis, a subset of venous endothelial cells of the cardinal vein express Prox1 and migrate out to form rudimentary lymphatic vessels. It is known that these Prox1-positive cells downregulate the expression of genes associated with venous endothelial identify and upregulate gene expression signatures consistent with LECs. However, the exact mechanisms underlying Prox1 mediated LEC differentiation are not known. We previously showed that Prox1 physically interacts with venous endothelial cell fate regulator, COUP-TFII. This preliminary work suggests that in addition to driving venous endothelial cell differentiation, COUP-TFII, also works in concert with Prox1 to establish and maintain the LEC lineage, which is the basis for the hypothesis of the proposed study. The concept that the key molecular regulator of venous endothelial cell identity plays an essential role in lymphatic development is of great interest and highlights the close histogenetic relationship between the two vascular systems. By dissecting the molecular interactions between Prox1 and COUP-TFII during LEC development, this proposal aims to elucidate the gene regulatory networks that orchestrate endothelial cell differentiation and advance our understanding of arteriovenous-lymphatic vascular development and disease.