Essential role for sphingosine kinases in neural and vascular development.
Sphingosine-1-phosphate (S1P), an important sphingolipid metabolite, regulates diverse cellular processes, including cell survival, growth, and differentiation. Here we show that S1P signaling is critical for neural and vascular development. Sphingosine kinase-null mice exhibited a deficiency of S1P which severely disturbed neurogenesis, including neural tube closure, and angiogenesis and caused embryonic lethality. A dramatic increase in apoptosis and a decrease in mitosis were seen in the developing nervous system. S1P(1) receptor-null mice also showed severe defects in neurogenesis, indicating that the mechanism by which S1P promotes neurogenesis is, in part, signaling from the S1P(1) receptor. Thus, S1P joins a growing list of signaling molecules, such as vascular endothelial growth factor, which regulate the functionally intertwined pathways of angiogenesis and neurogenesis. Our findings also suggest that exploitation of this potent neuronal survival pathway could lead to the development of novel therapeutic approaches for neurological diseases.
Mizugishi
Kiyomi
K
Genetics of Development and Disease Branch, NIDDK, National Institutes of Health, Bethesda, MD 20892-1821, USA.
Yamashita
Tadashi
T
Olivera
Ana
A
Miller
Georgina F
GF
Spiegel
Sarah
S
Proia
Richard L
RL
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001808:Blood Vessels / Q000002:abnormalities / Q000196:embryology* / Q000201:enzymology; D008246:Lysophospholipids / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis / Q000235:genetics; D018919:Neovascularization, Physiologic / Q000235:genetics; D009420:Nervous System / Q000196:embryology* / Q000201:enzymology; D009436:Neural Tube Defects / Q000201:enzymology / Q000235:genetics*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000502:physiology*; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D000099157:Sphingosine Kinase
D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate