RRC ID 6019
Author Ichise T, Yoshida N, Ichise H.
Title H-, N- and Kras cooperatively regulate lymphatic vessel growth by modulating VEGFR3 expression in lymphatic endothelial cells in mice.
Journal Development
Abstract Mammalian Ras, which is encoded by three independent genes, has been thought to be a versatile component of intracellular signalling. However, when, where and how Ras signalling plays essential roles in development and whether the three Ras genes have overlapping functions in particular cells remain unclear. Here, we show that the three Ras proteins dose-dependently regulate lymphatic vessel growth in mice. We find that lymphatic vessel hypoplasia is a common phenotype in Ras compound knockout mice and that overexpressed normal Ras in an endothelial cell lineage selectively causes lymphatic vessel hyperplasia in vivo. Overexpression of normal Ras in lymphatic endothelial cells leads to sustained MAPK activation, cellular viability and enhanced endothelial network formation under serum-depleted culture conditions in vitro, and knockdown of endogenous Ras in lymphatic endothelial cells impairs cell proliferation, MAPK activation, cell migration and endothelial network formation. Ras overexpression and knockdown result in up- and downregulation of vascular endothelial growth factor receptor (VEGFR) 3 expression, respectively, in lymphatic endothelial cells in vitro. The close link between Ras and VEGFR3 in vitro is consistent with the result that Ras knockout and transgenic alleles are genetic modifiers in lymphatic vessel hypoplasia caused by Vegfr3 haploinsufficiency. Our findings demonstrate a cooperative function of the three Ras proteins in normal development, and also provide a novel aspect of VEGFR3 signalling modulated by Ras in lymphangiogenesis.
Volume 137(6)
Pages 1003-13
Published 2010-3
DOI 10.1242/dev.043489
PII 137/6/1003
PMID 20179099
MeSH Animals Cells, Cultured Embryo, Mammalian Endothelial Cells / metabolism* Endothelial Cells / physiology Female Gene Expression Regulation, Developmental Genes, ras / physiology* Lymphangiogenesis / genetics* Lymphatic Vessels / embryology Lymphatic Vessels / metabolism Male Mice Mice, Inbred C57BL Mice, Inbred DBA Mice, Inbred ICR Mice, Transgenic Vascular Endothelial Growth Factor Receptor-3 / genetics* Vascular Endothelial Growth Factor Receptor-3 / metabolism
IF 5.413
Times Cited 28
Mice FLP66 mouse