title: 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(-/-) versus wild-type mice. p53(-/-) 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(-/-) 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(-/-) mice, while, similarly, p53 expression in p53(-/-) 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.
authors.affiliation: Laboratory for NeuroRegeneration and Repair, Center for Neurology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors.forename: Elisa M
authors.initials: EM
authors.lastname: Floriddia
authors.forename: Khizr I
authors.initials: KI
authors.lastname: Rathore
authors.forename: Andrea
authors.initials: A
authors.lastname: Tedeschi
authors.forename: Giorgia
authors.initials: G
authors.lastname: Quadrato
authors.forename: Anja
authors.initials: A
authors.lastname: Wuttke
authors.forename: Jan-Matthis
authors.initials: JM
authors.lastname: Lueckmann
authors.forename: Kristina A
authors.initials: KA
authors.lastname: Kigerl
authors.forename: Phillip G
authors.initials: PG
authors.lastname: Popovich
authors.forename: Simone
authors.initials: S
authors.lastname: Di Giovanni
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002921:Cicatrix / Q000473:pathology; D002818:Cordotomy; D005106:Exploratory Behavior / Q000502:physiology; D016158:Genes, p53; D006358:Hot Temperature; D007794:Lameness, Animal / Q000209:etiology / Q000503:physiopathology; D008124:Locomotion / Q000502:physiology*; D008262:Macrophage Activation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000473:pathology; D009473:Neuronal Plasticity / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D011712:Pyramidal Tracts / Q000473:pathology; D020127:Recovery of Function; D012183:Retrograde Degeneration; D012684:Sensory Thresholds; D059326:Serotonergic Neurons / Q000502:physiology; D013119:Spinal Cord Injuries / Q000235:genetics / Q000503:physiopathology*; D058630:Spinal Cord Regeneration / Q000235:genetics / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000502:physiology*
chemical_list: D016159:Tumor Suppressor Protein p53