Differential expression of (dihydro)ceramide synthases in mouse brain: oligodendrocyte-specific expression of CerS2/Lass2

Abstract

Synthesis of dihydroceramide is catalyzed by a family of (dihydro)ceramide synthases (CerS), first identified in yeast as longevity-assurance genes. Six members (CerS1-6; Lass1-6) of this gene family have been identified in mammals. We examined expression of CerS genes during postnatal development in mouse brain by means of Northern blot analysis, real-time RT-PCR, and in situ-hybridization. In situ-hybridization experiments showed that CerS1 was the predominant CerS in neurons throughout the brain. This observation is in line with the high levels of C18:0-ceramide in neurons and the substrate specificity of CerS1. A similar distribution, but lower expression levels, were found for CerS4 and CerS6. Only low or undetectable amounts of CerS1, CerS4 and CerS6 were, however, present in white matter. In contrast, CerS5 mRNA was detected in most cells within gray and white matter of all brain regions, suggesting ubiquitous expression of this palmitoyl-CoA specific CerS. Expression of CerS2 was transiently increased during the period of active myelination. Furthermore, expression of CerS2 was specifically localized to white matter tracts of the brain. Furthermore, CerS2 was the predominant CerS in Schwann cells of sciatic nerves. These data suggest that CerS2 is important for the synthesis of dihydroceramide used for synthesis of myelin sphingolipids.

Ectopic expression of ceramide synthase 2 in neurons suppresses neurodegeneration induced by ceramide synthase 1 deficiency

“…1C). In agreement with previous reports (17), in wild-type mice, CerS2 is only expressed in oligodendrocytes [adenomatous polyposis coli (APC)-positive] (Fig. 1 D-F), but not neurons such as Purkinje cells (IP3R1-positive) and granule neurons in the cerebellum ( Fig.…”

“…Also, it is not known whether ceramide species with different fatty acyl chains are interchangeable, nor do we know whether different ceramide synthases can be functionally interchangeable. To answer these questions, we set out to uncouple the production of C 18 ceramide with accumulation of LCBs by modulating ceramide biosynthesis in Cers1-deficient mutant brains through ectopic expression of the nonneuronal CerS2 that produces C 22 and C 24 instead of C 18 ceramides in the neurons (16,17).…”

“…CerS1-CerS6 also display different expression patterns. For instance, CerS1 produces C 18 ceramide and is neuron-specific in the brain, whereas CerS2 synthesizes C 22 and C 24 ceramides but is mainly present in oligodendrocytes in the brain (16,17).A Cers1 polymorphism resulting in increased CerS1 activity has been shown to correlate with enhanced longevity in humans (18). Conversely, a mutation reducing CerS1 activity has been associated with myoclonus epilepsy and dementia (19).…”

“…CerS1-CerS6 also display different expression patterns. For instance, CerS1 produces C 18 ceramide and is neuron-specific in the brain, whereas CerS2 synthesizes C 22 and C 24 ceramides but is mainly present in oligodendrocytes in the brain (16,17).…”

Encephalopathy Caused by Ablation of Very Long Acyl Chain Ceramide Synthesis May Be Largely Due to Reduced Galactosylceramide Levels

“…We have now examined brain abnormalities in the CerS2-null mouse. Although CerS2 mRNA expression levels are significantly lower in the whole brain than in the liver (12), it might be expressed at higher levels in a subset of brain cells, such as oligodendrocytes (16), and SLs containing very long acyl chain fatty acids are abundant in white matter and in myelin (17,18), suggesting a key role for CerS2 in these cells and brain regions. A previous report demonstrated that CerS2-null mice exhibit myelin defects as well as cerebellar degeneration at 9 months of age and cell loss in the hippocampus (19).…”