Sphk2 deficiency induces thrombocytopenia by redirection of sphingosine to Sphk1. (A-B) Platelet counts and MPV from Sphk2 heterozygous intercrosses in C57BL/6J:129SVJ mixed background. (B) Effect of MK (Pf4Cre)- and lymphatic endothelium/CD45+ (Lyve1Cre)–selective Sphk2 deletion on platelet counts. (C) Thrombocytopenia in Sphk2^−/− mice could be explained by redistribution of sphingosine to Sphk1 rather than by loss of Sphk2-derived S1P. This, in turn, could impair MK maturation by a receptor-dependent mechanism after S1P export by Spns2 or Mfsd2b, depending on cell type. (D) Impact of Sphk2 deficiency on the expression of Sphks and S1PRs and levels of sphingosine in total bone marrow cells (S1P was below the detection threshold). (E) Effect of deletion of Sphk1 in Mx1Cre-sensitive cells on Sphk2 deficiency-induced thrombocytopenia and MPV. (F) Effect of transplantation of BM cells from mice lacking Sphk1&2 in Mx1Cre-sensitive cells to lethally irradiated wild-type recipients and vice versa on platelet counts in the host. Note that the rescue conferred by Sphk1 deficiency is BM cell-derived, as the Sphk2^−/− phenotype itself.²²  (G) Effect of deletion of Sphk1 in MKs on Sphk2 deficiency-induced thrombocytopenia and MPV. (H) Effect of compound Sphk1 deficiency on MKP and platelet life span in Sphk2^−/− mice. Statistical analyses by Mann-Whitney U test or 2-way analysis of variance.