Endothelial ERK signaling controls lymphatic fate specification

• Published in: The Journal of clinical investigation Vol. 123; no. 3; pp. 1202 - 1215
• Main Authors: Deng, Yong, Atri, Deepak, Eichmann, Anne, Simons, Michael
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.03.2013
• Subjects: Animals; Aorta - pathology; Biomedical research; Body Patterning; Butadienes - pharmacology; Cells, Cultured; Cellular signal transduction; Development and progression; Edema; Endothelium, Lymphatic - embryology; Endothelium, Lymphatic - pathology; Extracellular signal-regulated kinases; Extracellular Signal-Regulated MAP Kinases - antagonists & inhibitors; Extracellular Signal-Regulated MAP Kinases - metabolism; Female; Gene Expression; Gene Expression Regulation, Developmental; Genetic aspects; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Human Umbilical Vein Endothelial Cells - metabolism; Human Umbilical Vein Endothelial Cells - physiology; Humans; Kinases; Lymphangiectasis - genetics; Lymphangiectasis - metabolism; Lymphangiectasis - pathology; Lymphangiogenesis; Lymphatic system; Male; MAP Kinase Signaling System; Mice; Mice, Transgenic; Mutation; Mutation, Missense; Nitriles - pharmacology; Noonan syndrome; Phosphorylation; Physiological aspects; Proto-Oncogene Proteins c-akt - metabolism; Proto-Oncogene Proteins c-raf - genetics; Proto-Oncogene Proteins c-raf - metabolism; SOXF Transcription Factors - genetics; SOXF Transcription Factors - metabolism; Transgenic animals; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Up-Regulation; Vascular Endothelial Growth Factor Receptor-3 - metabolism; Veins & arteries
• ISSN: 0021-9738; 1558-8238; 1558-8238
• DOI: 10.1172/JCI63034

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 (RAF1(S259A)) that is associated with Noonan syndrome. Expression of mutant RAF1(S259A) 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 RAF1(S259A). 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.