RXRα Blocks Nerve Regeneration after Spinal Cord Injury by Targeting p66shc

Nerve regeneration after spinal cord injury is regulated by many factors. Studies have found that the expression of retinoid X receptor α (RXR α ) does not change significantly after spinal cord injury but that the distribution of RXR α in cells changes significantly. In undamaged tissues, RXR α is distributed in motor neurons and the cytoplasm of glial cells. RXR α migrates to the nucleus of surviving neurons after injury, indicating that RXR α is involved in the regulation of gene expression after spinal cord injury. p66shc is an important protein that regulates cell senescence and oxidative stress. It can induce the apoptosis and necrosis of many cell types, promoting body aging. The absence of p66shc enhances the resistance of cells to reactive oxygen species (ROS) and thus prolongs life. It has been found that p66shc deletion can promote hippocampal neurogenesis and play a neuroprotective role in mice with multiple sclerosis. To verify the function of RXR α after spinal cord injury, we established a rat T9 spinal cord transection model. After RXR α agonist or antagonist administration, we found that RXR α agonists inhibited nerve regeneration after spinal cord injury, while RXR α antagonists promoted the regeneration of injured neurites and the recovery of motor function in rats. The results showed that RXR α played an impeding role in repair after spinal cord injury. Immunofluorescence staining showed that p66shc expression was upregulated in neurons after spinal cord injury ( in vivo and in vitro ) and colocalized with RXR α . RXR α overexpression in cultured neurons promoted the expression of p66shc, while RXR α interference inhibited the expression of p66shc. Using a luciferase assay, we found that RXR α could bind to the promoter region of p66shc and regulate the expression of p66shc, thereby regulating nerve regeneration after spinal cord injury. The above results showed that RXR α inhibited nerve regeneration after spinal cord injury by promoting p66shc expression, and interference with RXR α or p66shc promoted functional recovery after spinal cord injury.