H-, N- and Kras cooperatively regulate lymphatic vessel growth by modulating VEGFR3 expression in lymphatic endothelial cells in mice.
Development
; 137(6): 1003-13, 2010 Mar.
Article
en En
| MEDLINE
| ID: mdl-20179099
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Genes ras
/
Receptor 3 de Factores de Crecimiento Endotelial Vascular
/
Células Endoteliales
/
Linfangiogénesis
Límite:
Animals
Idioma:
En
Revista:
Development
Asunto de la revista:
BIOLOGIA
/
EMBRIOLOGIA
Año:
2010
Tipo del documento:
Article
País de afiliación:
Japón