Molecular Basis of Nuchal Edema

描述（由申请方提供）：颈部水肿（NE）是由于人类妊娠期间异常液体积聚引起的胎儿颈部后部组织肿胀，与染色体非整倍性胎儿相关。NE可以通过超声进行临床诊断，并且NE的测量（也称为颈项透性测量）已经被广泛接受为标准产前筛查方法，以评估胎儿具有染色体异常的风险。研究表明，超过80%的NE胎儿携带染色体异常，如唐氏综合征。虽然已报道NE与淋巴系统发育紊乱有关，但NE的分子基础目前尚不清楚。在这个提议中，我们提供了我们的初步证据，Notch信号在人类21三体唐氏综合征胎儿和他们的小鼠模型，16三体小鼠胚胎，表现出NE的淋巴系统失调。先前的研究表明Notch信号在指定动脉细胞命运中起着重要作用。同时，我们发现Notch可以重编程淋巴管内皮细胞（LECs），使其放弃正常的淋巴管分化程序，并采取动脉内皮细胞的命运。有趣的是，据报道，在核受体COUP-TFII敲除小鼠的静脉室中发生了类似的异常动脉化，这一发现表明COUP-TFII在静脉中的Notch抑制中起关键作用。我们还发现，两个唐氏综合征相关基因DSCR 1和Dyrk 1a，异位表达在原发性LEC，下调COUP-TFII。基于这些数据，我们现在建立了NE分子基础的新模型：DSCR 1和Dyrk 1a基因剂量的增加导致唐氏综合征胎儿LEC中COUP-TFII的下调和随后的Notch信号的激活，并且失调的Notch信号诱导发育中的淋巴细胞的病理性动脉化，其破坏胚胎组织液稳态，导致NE。在这个建议中，我们建议进一步剖析发展中动脉粥样硬化的病理动脉化的分子机制。我们提出的研究结果不仅将推进我们目前对动脉-静脉-淋巴管内皮细胞命运规范发育程序的分子机制的理解，而且还将为人类发育过程中的其他血管缺陷提供重要的见解。公共卫生相关性：胎儿颈部水肿（Nuchal edema，NE）是妊娠期胎儿颈部组织异常水肿的一种表现，目前已被公认为产前诊断胎儿染色体异常（包括唐氏综合征）的重要指标。尽管如此重要，异常胚胎液体积聚的分子基础仍然未知。在这个建议中，我们提供了我们的证据，因果关系连接NE与失调的Notch信号，并建议进一步剖析NE的分子机制。

DESCRIPTION (provided by applicant): Nuchal edema (NE) is a tissue swelling on the back of the neck of fetus due to an abnormal fluid accumulation during human pregnancy and has been associated with fetuses having chromosomal aneuploidy. NE can be clinically diagnosed by ultrasound and the measurement of NE, also called nuchal translucency measurement, has been widely accepted as a standard prenatal screening method to assess the risk of the fetus having chromosomal abnormalities. Studies show that more than 80% of NE fetuses carry chromosomal abnormalities such as Down syndrome. Although NE has been reported to be associated with disturbed development of the lymphatic system, the molecular basis of NE is currently unknown. In this proposal, we provide our preliminary evidence that Notch signal is dysregulated in the lymphatic system of human trisomy 21 Down syndrome fetuses and their mouse model, trisomy 16 mice embryos that exhibit NE. Previous studies show that Notch signal plays an essential role in specifying arterial cell fate. Consistently, we found that Notch can reprogram lymphatic endothelial cells (LECs) to abort the normal lymphatic differentiation program and adopt the arterial endothelial cell fate. Interestingly, a similar abnormal arterialization has been reported to occur in the venous compartment of knockout mice for the nuclear receptor COUP-TFII, a finding that indicates the key role of COUP-TFII in Notch repression in the veins. We also discovered that two Down syndrome-associated genes DSCR1 and Dyrk1a, when ectopically expressed in primary LECs, down-regulate COUP-TFII. Based on these data, we now build a novel model for the molecular basis of NE: Increased gene dosage of DSCR1 and Dyrk1a results in down-regulation of COUP- TFII and subsequent activation of Notch signal in LECs of Down syndrome fetuses, and the dysregulated Notch signal induces a pathological arterialization of the developing lymphatics, which fails embryonic tissue fluid homeostasis, causing NE. In this proposal, we propose to further dissect the molecular mechanism underlying the pathological arterialization of developing lymphatics. The outcome of our proposed studies will not only advance our current understanding of the molecular mechanism underlying the developmental programs for the arterio-venous-lymphatic endothelial cell fate specification, but also provide important insights into other vascular defects during human development. PUBLIC HEALTH RELEVANCE: Nuchal edema (NE) is a tissue swelling in the back of the neck of fetus due to an abnormal fluid accumulation during human pregnancy and is now accepted as an important prenatal diagnostic factor to assess the risk of the fetus for having chromosomal abnormalities including Down syndrome. Despite this importance, the molecular basis for the abnormal embryonic fluid accumulation remains unknown. In this proposal, we provide our evidences that causatively link NE with dysregulated Notch signaling and propose to further dissect the molecular mechanism for NE.