Lysophospholipid signaling in human neural progenitors

Abstract

Recent studies have shown that the fungal metabolite Fumonisin B1 (FB1) and the immunomodulatory drug FTY720 cause neural tube defects in mice. Both drugs inhibit ceramide synthase, resulting in an accumulation of sphingosine 1‐phosphate (S1P) and sphinganine 1‐phosphate (Sa1P) which are agonists for G‐protein coupled S1P receptors (S1PR). S1PRs are key regulators of neural development, suggesting that FB1 or FTY720 may cause developmental toxicity by altering signaling through S1PR. We have recently described S1P signaling pathways in human embryonic stem cell‐derived neuroepithelial cells (hES‐NEP). The goal of this project is to define the effects of FTY720 and FB1 on hES‐NEP cells, and establish this system as a platform in which to define the mechanism of lysophospholipid signaling in neural development. In the current study, we show that treatment of hES‐NEP with FB1 or FTY720 recapitulates the alterations in lipid profiles observed in‐vivo, resulting in marked increases in Sphinganine and Sa1P. Further, FTY720 is phosphorylated to the S1P receptor agonist FTY720‐P in hES‐NEP cells. Like S1P, both Sa1P and FTY720‐P stimulate activation of phospholipase C and inhibition of adenylyl cyclase, but with distinct rank order potencies and sensitivity to receptor and G‐protein inhibitors, suggesting these metabolites have unique signaling properties in human neural progenitors.Funding for this work is provided by the NIH and the University of Georgia.