ZFIN ID: ZDB-PUB-180825-3
Specific oxylipins enhance vertebrate hematopoiesis via the receptor GPR132
Lahvic, J.L., Ammerman, M., Li, P., Blair, M.C., Stillman, E.R., Fast, E.M., Robertson, A.L., Christodoulou, C., Perlin, J.R., Yang, S., Chiang, N., Norris, P.C., Daily, M.L., Redfield, S.E., Chan, I.T., Chatrizeh, M., Chase, M.E., Weis, O., Zhou, Y., Serhan, C.N., Zon, L.I.
Date: 2018
Source: Proceedings of the National Academy of Sciences of the United States of America   115(37): 9252-9257 (Journal)
Registered Authors: Perlin, Julie, Zhou, Yi, Zon, Leonard I.
Keywords: GPCR, free fatty acid, hematopoiesis, zebrafish
MeSH Terms:
  • Animals
  • Cell Cycle Proteins/genetics
  • Cell Cycle Proteins/metabolism*
  • Cells, Cultured
  • Hematopoiesis/drug effects*
  • Hematopoiesis/genetics
  • Mice
  • Mice, Knockout
  • Oxylipins*/chemistry
  • Oxylipins*/pharmacology
  • Receptors, G-Protein-Coupled/genetics
  • Receptors, G-Protein-Coupled/metabolism*
  • Signal Transduction/drug effects*
  • Signal Transduction/genetics
  • Structure-Activity Relationship
  • Zebrafish
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
PubMed: 30139917 Full text @ Proc. Natl. Acad. Sci. USA
Epoxyeicosatrienoic acids (EETs) are lipid-derived signaling molecules with cardioprotective and vasodilatory actions. We recently showed that 11,12-EET enhances hematopoietic induction and engraftment in mice and zebrafish. EETs are known to signal via G protein-coupled receptors, with evidence supporting the existence of a specific high-affinity receptor. Identification of a hematopoietic-specific EET receptor would enable genetic interrogation of EET signaling pathways, and perhaps clinical use of this molecule. We developed a bioinformatic approach to identify an EET receptor based on the expression of G protein-coupled receptors in cell lines with differential responses to EETs. We found 10 candidate EET receptors that are expressed in three EET-responsive cell lines, but not expressed in an EET-unresponsive line. Of these, only recombinant GPR132 showed EET-responsiveness in vitro, using a luminescence-based β-arrestin recruitment assay. Knockdown of zebrafish gpr132b prevented EET-induced hematopoiesis, and marrow from GPR132 knockout mice showed decreased long-term engraftment capability. In contrast to high-affinity EET receptors, GPR132 is reported to respond to additional hydroxy-fatty acids in vitro, and we found that these same hydroxy-fatty acids enhance hematopoiesis in the zebrafish. We conducted structure-activity relationship analyses using both cell culture and zebrafish assays on diverse medium-chain fatty acids. Certain oxygenated, unsaturated free fatty acids showed high activation of GPR132, whereas unoxygenated or saturated fatty acids had lower activity. Absence of the carbon-1 position carboxylic acid prevented activity, suggesting that this moiety is required for receptor activation. GPR132 responds to a select panel of oxygenated polyunsaturated fatty acids to enhance both embryonic and adult hematopoiesis.