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 (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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Aorta / pathology
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Body Patterning
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Butadienes / pharmacology
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Cells, Cultured
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Endothelium, Lymphatic / embryology
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Endothelium, Lymphatic / pathology*
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Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Female
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Gene Expression
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Gene Expression Regulation, Developmental
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Human Umbilical Vein Endothelial Cells / metabolism*
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Human Umbilical Vein Endothelial Cells / physiology
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Humans
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Lymphangiectasis / genetics
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Lymphangiectasis / metabolism
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Lymphangiectasis / pathology
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Lymphangiogenesis*
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MAP Kinase Signaling System*
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Male
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Mice
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Mice, Transgenic
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Mutation, Missense
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Nitriles / pharmacology
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Proto-Oncogene Proteins c-akt / metabolism
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Proto-Oncogene Proteins c-raf / genetics
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Proto-Oncogene Proteins c-raf / metabolism
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SOXF Transcription Factors / genetics
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SOXF Transcription Factors / metabolism
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism
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Up-Regulation
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Vascular Endothelial Growth Factor Receptor-3 / metabolism
Substances
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Butadienes
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Homeodomain Proteins
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Nitriles
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SOXF Transcription Factors
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Sox18 protein, mouse
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Tumor Suppressor Proteins
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U 0126
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prospero-related homeobox 1 protein
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Vascular Endothelial Growth Factor Receptor-3
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Proto-Oncogene Proteins c-akt
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Proto-Oncogene Proteins c-raf
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Extracellular Signal-Regulated MAP Kinases