Abstract
Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid involved in immunity, inflammation, angiogenesis, and cancer. S1P lyase (SPL) is the essential enzyme responsible for S1P degradation. SPL augments apoptosis and is down-regulated in cancer. SPL generates a S1P chemical gradient that promotes lymphocyte trafficking and as such is being targeted to treat autoimmune diseases. Despite growing interest in SPL as a disease marker, antioncogene, and pharmacological target, no comprehensive characterization of SPL expression in mammalian tissues has been reported. We investigated SPL expression in developing and adult mouse tissues by generating and characterizing a β-galactosidase-SPL reporter mouse combined with immunohistochemistry, immunoblotting, and enzyme assays. SPL was expressed in thymic and splenic stromal cells, splenocytes, Peyer's Patches, colonic lymphoid aggregates, circulating T and B lymphocytes, granulocytes, and monocytes, with lowest expression in thymocytes. SPL was highly expressed within the CNS, including arachnoid lining cells, spinal cord, choroid plexus, trigeminal nerve ganglion, and specific neurons of the olfactory bulb, cerebral cortex, midbrain, hindbrain, and cerebellum. Expression was detected in brown adipose tissue, female gonads, adrenal cortex, bladder epithelium, Harderian and preputial glands, and hair follicles. This unique expression pattern suggests SPL has many undiscovered physiological functions apart from its role in immunity.
Highlights
Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid involved in immunity, inflammation, angiogenesis, and cancer
sphingosine-1-phosphate receptor (S1PR) signaling is critical for development, as demonstrated by the embryonic lethal phenotype of S1PR1 knockout mice, due to severe hemorrhage associated with impaired vascular maturation [4]
Mice heterozygous for the S1P lyase (SPL) allele containing the reporter are born at expected mendelian frequency, exhibit no developmental or other phenotypes, and have normal reproductive function and lifespan, similar to mice heterozygous for a Sgpl1 null allele
Summary
Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid involved in immunity, inflammation, angiogenesis, and cancer. Sphingosine-1-phosphate (S1P) is the final metabolic product of sphingolipid degradation It circulates in the blood and lymph bound to lipoproteins and functions as a ligand for a family of five differentially expressed G proteincoupled receptors, the S1P receptors (S1PRs) [1, 2]. Acting through these receptors and the downstream signaling events mediated by them, S1P influences cell migration, survival, and stress responses [3]. The enzyme is conserved from yeast to humans, and mutants in various model organisms have revealed phenotypes including abnormalities of growth regulation and carbon metabolism in Saccharomyces cerevisiae, developmental and migration defects in Dictyostelium discoideum, reproductive defects in Caenorhabditis elegans, and defects of reproductive organs and muscles in Drosophila melanogaster [32,33,34,35,36]
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