Abstract
BackgroundSchwann cells (SCs) are the cell type responsible for the formation of the myelin sheath in the peripheral nervous system (PNS). As retinoic acid (RA) and other retinoids have a profound effect as regulators of the myelination program, we sought to investigate how their nuclear receptors levels were regulated in this cell type.Methodology/Principal FindingsIn the present study, by using Schwann cells primary cultures from neonatal Wistar rat pups, as well as myelinating cocultures of Schwann cells with embryonic rat dorsal root ganglion sensory neurons, we have found that sustained expression of RXR-γ depends on the continuous presence of a labile activator, while axonal contact mimickers produced an increase in RXR-γ mRNA and protein levels, increment that could be prevented by RA. The upregulation by axonal contact mimickers and the transcriptional downregulation by RA were dependent on de novo protein synthesis and did not involve changes in mRNA stability. On the other hand, RAR-β mRNA levels were only slightly modulated by axonal contact mimickers, while RA produced a strong transcriptional upregulation that was independent of de novo protein synthesis without changes in mRNA stability.Conclusions/SignificanceAll together, our results show that retinoid receptors are regulated in a complex manner in Schwann cells, suggesting that they could have a prominent role as regulators of Schwann cell physiology.
Highlights
All-trans-retinoic acid (RA) and other retinoids are potent regulators of morphogenesis, cell growth and differentiation, especially in the nervous system, where their abundance is comparatively very high [1]
This is especially notorious for retinoid X receptor (RXR)-c, which was expressed at much higher levels in myelinating SC/dorsal root ganglia neurons (DRGN) cocultures than in isolated SCs or sensory neurons, in which it was present at very low levels (Fig. 1B)
The results shown in this work demonstrate that retinoid receptors are present in Schwann cells and that their expression levels are tightly regulated by retinoic acid itself as well as by agents that mimic axonal contact
Summary
All-trans-retinoic acid (RA) and other retinoids are potent regulators of morphogenesis, cell growth and differentiation, especially in the nervous system, where their abundance is comparatively very high [1]. RA induces neurite outgrowth and neuronal differentiation of several neural cell types, including embryonic and adult stem cells, dorsal root ganglia neurons (DRGN), or neuroblastoma cells [2,3,4]. The fact that retinoid receptors seem to be present on SC [11] suggests that RA could play a role in SC physiology during development or in pathological conditions during Wallerian degeneration and remyelination, and on axonal growth and regeneration. As retinoic acid (RA) and other retinoids have a profound effect as regulators of the myelination program, we sought to investigate how their nuclear receptors levels were regulated in this cell type
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