Regulation of retinoic acid receptors alpha, beta and retinoid X receptor alpha after sciatic nerve injury.

Cell culture experiments indicated that activation of the retinoic acid signaling system is involved in axonal regeneration. This hypothesis was tested with sciatic nerve injury in the rat. Since the effect of retinoic acid is mediated via retinoic acid receptors and retinoid X receptors, we investigated mRNA and protein expression of these receptors during injury-induced degeneration and regeneration. Seven days after crush injury, transcript concentrations of all retinoic acid receptors and of retinoid X receptor alpha were significantly higher than in non-lesioned nerves. Protein levels of retinoic acid receptor alpha, retinoic acid receptor beta and retinoid X receptor alpha were upregulated 4, 7 and 14 days after injury. In degenerating nerves a significant increase of retinoic acid receptor alpha was detected 7 and 14 days, and of retinoic acid receptor beta 14 and 21 days after complete transection. Immunohistochemical staining of retinoid receptors revealed their expression in Schwann cells and macrophages. In addition, we observed that retinoic acid receptor alpha and retinoid X receptor alpha appeared in the cell nuclei of macrophages during the lesion-induced inflammatory reaction, and that retinoid X receptor alpha-staining co-localized with some regenerating axons. Experiments with Schwann cell primary cultures revealed an effect of retinoic acid on the expression of the neuregulin receptor ErbB3, suggesting that one function of retinoic acid consists in the regulation of neuroglial interactions after peripheral nerve injury.