Liver X Receptors differentially modulate central myelin gene mRNA levels in a region-, age- and isoform-specific manner

•LXR invalidation differentially affects mRNA amount of myelin genes in the major myelinated regions of the CNS.•LXR activation disturbs myelin gene mRNA amounts within several myelin-rich structures of the CNS.•LXRα and β isoforms expression level differs between the major myelinated regions of the CNS

Liver X Receptors (LXRs) α and β are nuclear receptors able to bind oxidative forms of cholesterol. They play important roles in the central nervous system (CNS), through their implication in a large variety of physiological and pathological processes among which modulation of cholesterol homeostasis and inflammation. Besides, we recently revealed their crucial role in myelination and remyelination in the cerebellum. Given the pleiotropic effects of such receptors on CNS functioning, we studied here the influence of LXRs on myelin gene mRNA accumulation in the major myelinated regions of the CNS in vivo.We show that both LXR isoforms differentially affect mRNA amount of myelin genes (PLP and MBP) in highly myelinated structures such as spinal cord, corpus callosum, optic nerve and cerebellum. In the adult, LXR activation by the synthetic agonist TO901317 significantly increases myelin gene mRNA amount in the cerebellum but not in the other regions studied. Invalidation of the sole LXRβ isoform leads to decreased PLP and MBP mRNA levels in all the structures except the spinal cord, while the knock out of both isoforms (LXR dKO) decreases myelin gene mRNA amounts in all the regions tested except the corpus callosum. Interestingly, during myelination process (post-natal day 21), both cerebellum and optic nerve display a decrease in myelin gene mRNA levels in LXR dKO mice. Concomitantly, PLP and MBP mRNA accumulation in the spinal cord is increased. Relative expression level of LXR isoforms could account for the differential modulation of myelin gene expression in the CNS.Altogether our results suggest that, within the CNS, each LXR isoform differentially influences myelin gene mRNA levels in a region- and age-dependant manner, participating in the fine regulation of myelin gene expression.

Graphical abstractVariation of mRNA levels of central myelin genes in different myelinated regions of the central nervous system in LXR dKO, WT treated with TO9, and LXR βKO compared to WT. T09: T0901317, LXR dKO: LXRα and β invalidation, LXRβKO: LXRβ invalidation WT: Wild-type.Download high-res image (152KB)Download full-size image