title: 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 (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.
authors: Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors: Yong
authors: Y
authors: Deng
authors: Deepak
authors: D
authors: Atri
authors: Anne
authors: A
authors: Eichmann
authors: Michael
authors: M
authors: Simons
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology; D019521:Body Patterning; D002070:Butadienes / Q000494:pharmacology; D002478:Cells, Cultured; D004729:Endothelium, Lymphatic / Q000196:embryology / Q000473:pathology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D008200:Lymphangiectasis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D042583:Lymphangiogenesis; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense; D009570:Nitriles / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics / Q000378:metabolism; D055760:SOXF Transcription Factors / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: D002070:Butadienes; D018398:Homeodomain Proteins; D009570:Nitriles; D055760:SOXF Transcription Factors; C490653:Sox18 protein, mouse; D025521:Tumor Suppressor Proteins; C113580:U 0126; D000098551:Prospero-Related Homeobox 1 Protein; D040321:Vascular Endothelial Growth Factor Receptor-3; D051057:Proto-Oncogene Proteins c-akt; D019908:Proto-Oncogene Proteins c-raf; D048049:Extracellular Signal-Regulated MAP Kinases
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