Edg-1, the G protein-coupled receptor for sphingosine-1-phosphate, is essential for vascular maturation.
Sphingolipid signaling pathways have been implicated in many critical cellular events. Sphingosine-1-phosphate (SPP), a sphingolipid metabolite found in high concentrations in platelets and blood, stimulates members of the endothelial differentiation gene (Edg) family of G protein-coupled receptors and triggers diverse effects, including cell growth, survival, migration, and morphogenesis. To determine the in vivo functions of the SPP/Edg signaling pathway, we disrupted the Edg1 gene in mice. Edg1(-/-) mice exhibited embryonic hemorrhage leading to intrauterine death between E12.5 and E14.5. Vasculogenesis and angiogenesis appeared normal in the mutant embryos. However, vascular maturation was incomplete due to a deficiency of vascular smooth muscle cells/pericytes. We also show that Edg-1 mediates an SPP-induced migration response that is defective in mutant cells due to an inability to activate the small GTPase, Rac. Our data reveal Edg-1 to be the first G protein-coupled receptor required for blood vessel formation and show that sphingolipid signaling is essential during mammalian development.
Liu
Y
Y
Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, Maryland 20892-1821, USA.
Wada
R
R
Yamashita
T
T
Mi
Y
Y
Deng
C X
CX
Hobson
J P
JP
Rosenfeldt
H M
HM
Nava
V E
VE
Chae
S S
SS
Lee
M J
MJ
Liu
C H
CH
Hla
T
T
Spiegel
S
S
Proia
R L
RL
D000818:Animals; D001808:Blood Vessels / Q000196:embryology; D002319:Cardiovascular System / Q000196:embryology*; D002465:Cell Movement; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006321:Heart / Q000196:embryology; D006720:Homozygote; D017874:Immediate-Early Proteins / Q000235:genetics*; D008246:Lysophospholipids; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000196:embryology*; D010641:Phenotype; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D049312:Receptors, Lysophospholipid; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology
D017874:Immediate-Early Proteins; D008246:Lysophospholipids; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D049312:Receptors, Lysophospholipid; C060506:sphingosine 1-phosphate; D019204:GTP-Binding Proteins; D013110:Sphingosine