Liver X receptor beta delays transformation of radial glial cells into astrocytes during mouse cerebral cortical development

摘要

Radial glial (RG) cells serve as stem cells to produce new born neurons and scaffolds for neuronal migration during corticogenesis. After neurogenesis and migration are completed, most RG cells transform into astrocytes. However, the mechanisms that determine how RG cells are transformed into astrocytes are not well understood. Using nestin as a specific marker for both RG cells and astrocytes, we found that loss of LXRp caused a reduction in the level of RG fibers and increase in the astrocytes. At the same time, we showed that the level of brain lipid-binding protein (BLBP), a RG-specific protein, was lower in the LXRp knockout (LXRbeta~(-/-)) mice than in the wild type (WT) littermates from E18.5 to P14, a time period when most of RG cells are transformed into astrocytes. However, loss of LXRp induced significant increase in the number of GFAP labeled astrocytes in the cerebral cortex. An increase of the transformation of RG cells into astrocytes in LXRbeta~(-/-) mice was further confirmed by the increased percentage of BLBP and GFAP double stained cells in the total BLBP positive cells of the Layer I and Layers V-VI. TGF-beta1 and Smad4 are thought to be involved in the transformation of RG cells into astrocytes. The expression levels of TGF-beta1 mRNA and Smad4 mRNA were significantly higher in the cerebral cortex of LXRbeta~(-/-) mice than that in the WT littermates at P2 and P7, but by P10 and P14, mRNA levels had normalized and no differences were observed between WT and LXRbeta~(-/-) mice. Taken together, our findings suggest that loss of LXRbeta accelerates the transformation of RG cells into astrocytes and that this acceleration may be correlated to higher levels TGF-beta1 and Smad4 in the cerebral cortex between P2 and P7.