Molecular Basis of Nuchal Edema

描述(申请人提供)：颈部水肿(NE)是胎儿颈部后部的一种组织肿胀，因人类妊娠期间液体异常堆积而引起，并与染色体非整倍体胎儿有关。临床上可以通过超声诊断NE，NE的测量也被称为颈部透明测量，已被广泛接受为评估胎儿染色体异常风险的一种标准产前筛查方法。研究表明，超过80%的NE胎儿携带唐氏综合症等染色体异常。尽管去甲肾上腺素已被报道与淋巴系统发育紊乱有关，但目前去甲肾上腺素的分子基础尚不清楚。在这项建议中，我们提供了我们的初步证据，即Notch信号在人类21三体唐氏综合征胎儿及其小鼠模型16三体小鼠胚胎的淋巴系统中调节失调。以往的研究表明，Notch信号在决定动脉细胞命运中起着至关重要的作用。我们一致地发现，Notch可以重新编程淋巴管内皮细胞(LECs)来中止正常的淋巴管分化程序，而采用动脉内皮细胞的命运。有趣的是，据报道，在核受体COUP-TFII基因敲除的小鼠的静脉腔中也发生了类似的异常动脉化，这一发现表明COUP-TFII在静脉Notch抑制中发挥了关键作用。我们还发现，两个唐氏综合征相关基因DSCR1和Dyrk1a，当在原代LEC中异位表达时，下调COUP-TFII。基于这些数据，我们现在建立了一个新的NE分子基础模型：DSCR1和Dyrk1a基因剂量增加导致Down综合征胎儿晶状体上皮细胞COUP-TFII下调并随后激活Notch信号，而异常调节的Notch信号导致发育中的淋巴管病理性动脉化，这导致胚胎组织液内环境不稳定，导致NE。在这项建议中，我们建议进一步剖析发育中淋巴管病理动脉化的分子机制。我们提出的研究结果不仅将促进我们目前对动-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，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：颈部水肿症是指在人类妊娠期间由于液体异常积聚而导致的胎儿颈部后部的一种组织肿胀，现已被公认为是评估胎儿患有包括唐氏综合症在内的染色体异常的风险的重要产前诊断因素。尽管这很重要，但胚胎积液异常的分子基础仍不清楚。在这项研究中，我们提供了去甲肾上腺素与Notch信号异常相关的证据，并建议进一步剖析去甲肾上腺素的分子机制。

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.