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Endothelial ERK signaling controls lymphatic fate specification
Yong Deng, … , Anne Eichmann, Michael Simons
Yong Deng, … , Anne Eichmann, Michael Simons
Published February 8, 2013
Citation Information: J Clin Invest. 2013;123(3):1202-1215. https://doi.org/10.1172/JCI63034.
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Research Article Vascular biology

Endothelial ERK signaling controls lymphatic fate specification

Abstract

Lymphatic vessels are thought to arise from PROX1-positive endothelial cells (ECs) in the cardinal vein in response to induction of SOX18 expression; however, the molecular event responsible for increased SOX18 expression has not been established. We generated mice with endothelial-specific, inducible expression of an RAF1 gene with a gain-of-function mutation (RAF1S259A) that is associated with Noonan syndrome. Expression of mutant RAF1S259A in ECs activated ERK and induced SOX18 and PROX1 expression, leading to increased commitment of venous ECs to the lymphatic fate. Excessive production of lymphatic ECs resulted in lymphangiectasia that was highly reminiscent of abnormal lymphatics seen in Noonan syndrome and similar “RASopathies.” Inhibition of ERK signaling during development abrogated the lymphatic differentiation program and rescued the lymphatic phenotypes induced by expression of RAF1S259A. These data suggest that ERK activation plays a key role in lymphatic EC fate specification and that excessive ERK activation is the basis of lymphatic abnormalities seen in Noonan syndrome and related diseases.

Authors

Yong Deng, Deepak Atri, Anne Eichmann, Michael Simons

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