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- Title
Dysregulated Notch signaling induces pathological arterialization of developing lymphatics in Down syndrome fetus.
- Authors
Jinjoo Kang; Van Den Akker, Nynke M. S.; Aguflar, Bernice; Wanli Tang; Kafka, Darren; Sunju Lee; Ramu, Swapnika; Ganesan, Sathish Kumar; Out, Hasan H.; Van Vugt, John M. G.; Shin, Jay W.; Dotto, G. Paolo; Detmar, Michael; Gittenberger-De Groot, Adriana C.; Young-Kwon Hong
- Abstract
Notch signaling plays an important role in arterial-venous specification during embryogenesis. However, the role of Notch signaling in lymphatic development is poorly understood. Here, we show that activated Notch and its downstream effectors, Hey1 and Hey2, repress the expression of the master control gene of lymphatic development Prox1, and induce arterial phenotypes in human lymphatic endothelial cells (LECs). We then translated our findings to define the molecular basis for the disturbed lymphatic development of nuchal edema (NE) of aneuploid human fetuses. We found that Hey1 was upregulated in LECs of developing jugular lymph sacs (JLS) of Down syndrome fetuses, whereas Prox1, LYVE-1 and podoplanin were down-regulated. Moreover, the arterial markers ephrinB2 and neuropilin-1 were upregulated and the venous marker EphB4 was transiently expressed. These data indicate that JLS endothelial ceils of NE fetuses arrested lymphatic differentiation program, regained venous phenotype and acquired arterial endothelial cell identity. We propose that dysregulated Notch signaling induces pathological arterialization of developing lymphatic vessels in human Down syndrome fetuses with NE.
- Subjects
NOTCH proteins; LYMPHATICS; FETUS; DOWN syndrome; GENE expression; PHENOTYPES; EDEMA
- Publication
FASEB Journal, 2007, Vol 21, Issue 5, pA15
- ISSN
0892-6638
- Publication type
Article