Marked perinatal lethality and cellular signaling deficits in mice null for the two sphingosine 1-phosphate (S1P) receptors, S1P2/LPB2/EDG-5 and S1P3/LPB3/EDG-3

Isao Ishii, Xiaoqin Ye, Beth Friedman, Shuji Kawamura, James J.A. Contos, Marcy A. Kingsbury, Amy H. Yang, Guangfa Zhang, Joan Heller Brown, Jerold Chun

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Abstract

Five cognate G protein-coupled receptors (SIP1-5) have been shown to mediate various cellular effects of sphingosine 1-phosphate (S1P). Here we report the generation of mice null for S1P2 and for both S1P2 and S1P3. S1P2-null mice were viable and fertile and developed normally. The litter sizes from S1P2S1P3 double-null crosses were remarkably reduced compared with controls, and double-null pups often did not survive through infancy, although double-null survivors lacked any obvious phenotype. Mouse embryonic fibroblasts (MEFs) were examined for the effects of receptor deletions on S1P signaling pathways. Wild-type MEFs were responsive to S1P in activation of Rho and phospholipase C (PLC), intracellular calcium mobilization, and inhibition of forskolin-activated adenylyl cyclase. S1P2-null MEFs showed a significant decrease in Rho activation, but no effect on PLC activation, calcium mobilization, or adenylyl cyclase inhibition. Double-null MEFs displayed a complete loss of Rho activation and a significant decrease in PLC activation and calcium mobilization, with no effect on adenylyl cyclase inhibition. These data extend our previous findings on S1P3-null mice and indicate preferential coupling of the S1P2 and S1P3 receptors to Rho and PLC/Ca2+ pathways, respectively. Although either receptor subtype supports embryonic development, deletion of both produces marked perinatal lethality, demonstrating an essential role for combined S1P signaling by these receptors.

Original languageEnglish
Pages (from-to)25152-25159
Number of pages8
JournalJournal of Biological Chemistry
Volume277
Issue number28
DOIs
Publication statusPublished - 2002 Jul 12

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Ishii, I., Ye, X., Friedman, B., Kawamura, S., Contos, J. J. A., Kingsbury, M. A., Yang, A. H., Zhang, G., Brown, J. H., & Chun, J. (2002). Marked perinatal lethality and cellular signaling deficits in mice null for the two sphingosine 1-phosphate (S1P) receptors, S1P2/LPB2/EDG-5 and S1P3/LPB3/EDG-3. Journal of Biological Chemistry, 277(28), 25152-25159. https://doi.org/10.1074/jbc.M200137200