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

Research output: Contribution to journalArticle

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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
Externally publishedYes

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Lysosphingolipid Receptors
Cell signaling
Type C Phospholipases
Fibroblasts
Chemical activation
Adenylyl Cyclases
Calcium
Colforsin
G-Protein-Coupled Receptors
Litter Size
Embryonic Development
sphingosine 1-phosphate
Phenotype

ASJC Scopus subject areas

  • Biochemistry

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

In: Journal of Biological Chemistry, Vol. 277, No. 28, 12.07.2002, p. 25152-25159.

Research output: Contribution to journalArticle

Ishii, I, Ye, X, Friedman, B, Kawamura, S, Contos, JJA, Kingsbury, MA, Yang, AH, Zhang, G, Brown, JH & 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, vol. 277, no. 28, pp. 25152-25159. https://doi.org/10.1074/jbc.M200137200
Ishii, Isao ; Ye, Xiaoqin ; Friedman, Beth ; Kawamura, Shuji ; Contos, James J A ; Kingsbury, Marcy A. ; Yang, Amy H. ; Zhang, Guangfa ; Brown, Joan Heller ; Chun, Jerold. / 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. In: Journal of Biological Chemistry. 2002 ; Vol. 277, No. 28. pp. 25152-25159.
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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.",
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AU - Ishii, Isao

AU - Ye, Xiaoqin

AU - Friedman, Beth

AU - Kawamura, Shuji

AU - Contos, James J A

AU - Kingsbury, Marcy A.

AU - Yang, Amy H.

AU - Zhang, Guangfa

AU - Brown, Joan Heller

AU - Chun, Jerold

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