Mice deficient in sphingosine kinase 1 are rendered lymphopenic by FTY720.
Sphingosine-1-phosphate (S1P), a lipid signaling molecule that regulates many cellular functions, is synthesized from sphingosine and ATP by the action of sphingosine kinase. Two such kinases have been identified, SPHK1 and SPHK2. To begin to investigate the physiological functions of sphingosine kinase and S1P signaling, we generated mice deficient in SPHK1. Sphk1 null mice were viable, fertile, and without any obvious abnormalities. Total SPHK activity in most Sphk1-/-tissues was substantially, but not completely, reduced indicating the presence of multiple sphingosine kinases. S1P levels in most tissues from the Sphk1-/- mice were not markedly decreased. In serum, however, there was a significant decrease in the S1P level. Although S1P signaling regulates lymphocyte trafficking, lymphocyte distribution was unaffected in lymphoid organs of Sphk1-/- mice. The immunosuppressant FTY720 was phosphorylated and elicited lymphopenia in the Sphk1 null mice showing that SPHK1 is not required for the functional activation of this sphingosine analogue prodrug. The results with these Sphk1 null mice reveal that some key physiologic processes that require S1P receptor signaling, such as vascular development and proper lymphocyte distribution, can occur in the absence of SPHK1.
Genetics of Development and Disease Branch, NIDDK and NIAMS, National Institutes of Health, Bethesda, Maryland 20892, USA.
Maria L
ML
Allende
Teiji
T
Sasaki
Hiromichi
H
Kawai
Ana
A
Olivera
Yide
Y
Mi
Gerhild
G
van Echten-Deckert
Richard
R
Hajdu
Mark
M
Rosenbach
Carol Ann
CA
Keohane
Suzanne
S
Mandala
Sarah
S
Spiegel
Richard L
RL
Proia
D000818:Animals; D001483:Base Sequence; D004247:DNA / Q000235:genetics; D000068876:Fingolimod Hydrochloride; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000633:toxicity; D008214:Lymphocytes / Q000187:drug effects / Q000502:physiology; D008231:Lymphopenia / Q000139:chemically induced / Q000201:enzymology / Q000209:etiology*; D008246:Lysophospholipids / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D011355:Prodrugs / Q000378:metabolism / Q000633:toxicity; D011409:Propylene Glycols / Q000378:metabolism / Q000633:toxicity*; D049349:Receptors, Lysosphingolipid / Q000378:metabolism; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D000099157:Sphingosine Kinase
D004247:DNA; D000068876:Fingolimod Hydrochloride; D007166:Immunosuppressive Agents; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D011355:Prodrugs; D011409:Propylene Glycols; D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate