RGD Reference Report - Endothelial ERK signaling controls lymphatic fate specification. - Rat Genome Database

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Endothelial ERK signaling controls lymphatic fate specification.

Authors: Deng, Yong  Atri, Deepak  Eichmann, Anne  Simons, Michael 
Citation: Deng Y, etal., J Clin Invest. 2013 Mar;123(3):1202-15. doi: 10.1172/JCI63034. Epub 2013 Feb 8.
RGD ID: 12910710
Pubmed: PMID:23391722   (View Abstract at PubMed)
PMCID: PMC3582116   (View Article at PubMed Central)
DOI: DOI:10.1172/JCI63034   (Journal Full-text)

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.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
RAF1HumanLymphangiectasis  ISORaf1 (Mus musculus)DNA:point mutation:exon :p.S259A (mouse)RGD 
Raf1RatLymphangiectasis  ISORaf1 (Mus musculus)DNA:point mutation:exon :p.S259A (mouse)RGD 
Raf1MouseLymphangiectasis  IMP DNA:point mutation:exon :p.S259A (mouse)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Raf1  (Raf-1 proto-oncogene, serine/threonine kinase)

Genes (Mus musculus)
Raf1  (v-raf-leukemia viral oncogene 1)

Genes (Homo sapiens)
RAF1  (Raf-1 proto-oncogene, serine/threonine kinase)


Additional Information