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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-CVS-P (50))
Program Officer
Oster-Granite, Mary Lou
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Southern California
Schools of Medicine
Los Angeles
United States
Zip Code
Choi, Dongwon; Ramu, Swapnika; Park, Eunkyung et al. (2016) Aberrant Activation of Notch Signaling Inhibits PROX1 Activity to Enhance the Malignant Behavior of Thyroid Cancer Cells. Cancer Res 76:582-93
Park, Dae-Young; Lee, Junyeop; Park, Intae et al. (2014) Lymphatic regulator PROX1 determines Schlemm's canal integrity and identity. J Clin Invest 124:3960-74
Lee, Yong Suk; Choi, Dongwon; Kim, Nam Yoon et al. (2014) CXCR2 inhibition enhances sulindac-mediated suppression of colon cancer development. Int J Cancer 135:232-7
Choi, Inho; Lee, Yong Suk; Chung, Hee Kyoung et al. (2013) Interleukin-8 reduces post-surgical lymphedema formation by promoting lymphatic vessel regeneration. Angiogenesis 16:29-44
Francois, Mathias; Short, Kieran; Secker, Genevieve A et al. (2012) Segmental territories along the cardinal veins generate lymph sacs via a ballooning mechanism during embryonic lymphangiogenesis in mice. Dev Biol 364:89-98
Choi, Inho; Lee, Sunju; Kyoung Chung, Hee et al. (2012) 9-cis retinoic acid promotes lymphangiogenesis and enhances lymphatic vessel regeneration: therapeutic implications of 9-cis retinoic acid for secondary lymphedema. Circulation 125:872-82
Aguilar, Berenice; Choi, Inho; Choi, Dongwon et al. (2012) Lymphatic reprogramming by Kaposi sarcoma herpes virus promotes the oncogenic activity of the virus-encoded G-protein-coupled receptor. Cancer Res 72:5833-42
Yoo, Jaehyuk; Lee, Ha Neul; Choi, Inho et al. (2012) Opposing regulation of PROX1 by interleukin-3 receptor and NOTCH directs differential host cell fate reprogramming by Kaposi sarcoma herpes virus. PLoS Pathog 8:e1002770
Choi, Inho; Chung, Hee Kyoung; Ramu, Swapnika et al. (2011) Visualization of lymphatic vessels by Prox1-promoter directed GFP reporter in a bacterial artificial chromosome-based transgenic mouse. Blood 117:362-5
Ning, Yan; Manegold, Philipp C; Hong, Young Kwon et al. (2011) Interleukin-8 is associated with proliferation, migration, angiogenesis and chemosensitivity in vitro and in vivo in colon cancer cell line models. Int J Cancer 128:2038-49

Showing the most recent 10 out of 18 publications