p53 Regulates the Neuronal Intrinsic and Extrinsic Responses Affecting the Recovery of Motor Function following Spinal Cord Injury

Abstract

Following spinal trauma, the limited physiological axonal sprouting that contributes to partial recovery of function is dependent upon the intrinsic properties of neurons as well as the inhibitory glial environment. The transcription factor p53 is involved in DNA repair, cell cycle, cell survival, and axonal outgrowth, suggesting p53 as key modifier of axonal and glial responses influencing functional recovery following spinal injury. Indeed, in a spinal cord dorsal hemisection injury model, we observed a significant impairment in locomotor recovery in p53 Ϫ/Ϫ versus wild-type mice. p53 Ϫ/Ϫ spinal cords showed an increased number of activated microglia/macrophages and a larger scar at the lesion site. Loss-and gain-of-function experiments suggested p53 as a direct regulator of microglia/macrophages proliferation. At the axonal level, p53 Ϫ/Ϫ mice showed a more pronounced dieback of the corticospinal tract (CST) and a decreased sprouting capacity of both CST and spinal serotoninergic fibers. In vivo expression of p53 in the sensorimotor cortex rescued and enhanced the sprouting potential of the CST in p53 Ϫ/Ϫ mice, while, similarly, p53 expression in p53 Ϫ/Ϫ cultured cortical neurons rescued a defect in neurite outgrowth, suggesting a direct role for p53 in regulating the intrinsic sprouting ability of CNS neurons. In conclusion, we show that p53 plays an important regulatory role at both extrinsic and intrinsic levels affecting the recovery of motor function following spinal cord injury. Therefore, we propose p53 as a novel potential multilevel therapeutic target for spinal cord injury.

PCAF-dependent epigenetic changes promote axonal regeneration in the central nervous system

“…Surgeries were performed as previously reported 40 . Briefly, mice were anesthetized and a T10 laminectomy was performed (B20 mm from the L4-L6 DRGs), the dura mater was removed, taking care of not damaging the spinal cord.…”

“…Mice with incomplete lesions were excluded. Staining for GFAP (1:2,000) was performed following the standard protocols 40 . Confocal laser scanning microscopy was performed using a Zeiss LSM700.…”

The intracellular domain of L1CAM binds to casein kinase 2α and is neuroprotective via inhibition of the tumor suppressors PTEN and p53

“…; Floriddia et al . ). Thus, inhibition of PTEN and p53 mediates beneficial functions in regeneration after trauma, which is also a characteristic feature of L1.…”

“…In addition to PTEN, the tumor suppressor p53 is also a substrate of CK2 (Martel et al 2006). Inhibition of CK2mediated phosphorylation of p53 reduces stability of p53 (Dixit et al 2012), and activation of p53 leads to neuronal cell death and loss of neurites (Saito et al 2000;Lau and Bading 2009;Murase et al 2011;Desplats et al 2012;Floriddia et al 2012;Engel et al 2013). p53 regulates neurite outgrowth and axonal regeneration via neurotrophinindependent signaling and post-translational control of growth cone remodeling (Di Giovanni et al 2006).…”

“…p53 regulates neurite outgrowth and axonal regeneration via neurotrophinindependent signaling and post-translational control of growth cone remodeling (Di Giovanni et al 2006). Like CK2, p53 is also implicated in neuronal survival and recovery after spinal cord injury (Saito et al 2000;Desplats et al 2012;Floriddia et al 2012). Thus, inhibition of PTEN and p53 mediates beneficial functions in regeneration after trauma, which is also a characteristic feature of L1.…”