title: The MDM4/MDM2-p53-IGF1 axis controls axonal regeneration, sprouting and functional recovery after CNS injury.
abstract: Regeneration of injured central nervous system axons is highly restricted, causing neurological impairment. To date, although the lack of intrinsic regenerative potential is well described, a key regulatory molecular mechanism for the enhancement of both axonal regrowth and functional recovery after central nervous system injury remains elusive. While ubiquitin ligases coordinate neuronal morphogenesis and connectivity during development as well as after axonal injury, their role specifically in axonal regeneration is unknown. Following a bioinformatics network analysis combining ubiquitin ligases with previously defined axonal regenerative proteins, we found a triad composed of the ubiquitin ligases MDM4, MDM2 and the transcription factor p53 (encoded by TP53) as a putative central signalling complex restricting the regeneration program. Indeed, conditional deletion of MDM4 or pharmacological inhibition of MDM2/p53 interaction in the eye and spinal cord promote axonal regeneration and sprouting of the optic nerve after crush and of supraspinal tracts after spinal cord injury. The double conditional deletion of MDM4-p53 as well as MDM2 inhibition in p53-deficient mice blocks this regenerative phenotype, showing its dependence upon p53. Genome-wide gene expression analysis from ex vivo fluorescence-activated cell sorting in MDM4-deficient retinal ganglion cells identifies the downstream target IGF1R, whose activity and expression was found to be required for the regeneration elicited by MDM4 deletion. Importantly, we demonstrate that pharmacological enhancement of the MDM2/p53-IGF1R axis enhances axonal sprouting as well as functional recovery after spinal cord injury. Thus, our results show MDM4-MDM2/p53-IGF1R as an original regulatory mechanism for CNS regeneration and offer novel targets to enhance neurological recovery.media-1vid110.1093/brain/awv125_video_abstractawv125_video_abstract.
authors.affiliation: 1 Laboratory for NeuroRegeneration and Repair, Centre for Neurology, Hertie Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany 2 Graduate School for Cellular and Molecular Neuroscience, University of Tuebingen, Tuebingen, Germany 3 German Centre for Neurodegenerative Diseases (DZNE), Tuebingen, Germany.
authors.forename: Yashashree
authors.initials: Y
authors.lastname: Joshi
authors.affiliation: 1 Laboratory for NeuroRegeneration and Repair, Centre for Neurology, Hertie Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany 2 Graduate School for Cellular and Molecular Neuroscience, University of Tuebingen, Tuebingen, Germany.
authors.forename: Marília Grando
authors.initials: MG
authors.lastname: Sória
authors.affiliation: 1 Laboratory for NeuroRegeneration and Repair, Centre for Neurology, Hertie Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Quadrato
authors.affiliation: 1 Laboratory for NeuroRegeneration and Repair, Centre for Neurology, Hertie Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany 2 Graduate School for Cellular and Molecular Neuroscience, University of Tuebingen, Tuebingen, Germany.
authors.forename: Gizem
authors.initials: G
authors.lastname: Inak
authors.affiliation: 1 Laboratory for NeuroRegeneration and Repair, Centre for Neurology, Hertie Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany 4 Molecular Neuroregeneration, Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK.
authors.forename: Luming
authors.initials: L
authors.lastname: Zhou
authors.affiliation: 4 Molecular Neuroregeneration, Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK.
authors.forename: Arnau
authors.initials: A
authors.lastname: Hervera
authors.affiliation: 1 Laboratory for NeuroRegeneration and Repair, Centre for Neurology, Hertie Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany.
authors.forename: Khizr I
authors.initials: KI
authors.lastname: Rathore
authors.affiliation: 1 Laboratory for NeuroRegeneration and Repair, Centre for Neurology, Hertie Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany 2 Graduate School for Cellular and Molecular Neuroscience, University of Tuebingen, Tuebingen, Germany.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Elnaggar
authors.forename: Magali
authors.initials: M
authors.lastname: Cucchiarini
authors.affiliation: 5 Centre of Experimental Orthopaedics, Saarland University Medical Centre, Homburg/Saar, Germany.
authors.forename: Cucchiarini
authors.initials: C
authors.lastname: Magali
authors.affiliation: 6 Laboratory for Molecular Cancer Biology, Department of Molecular and Developmental Genetics, VIB-K.U.Leuven, Leuven, Belgium.
authors.forename: Jeanne Christophe
authors.initials: JC
authors.lastname: Marine
authors.affiliation: 1 Laboratory for NeuroRegeneration and Repair, Centre for Neurology, Hertie Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany.
authors.forename: Radhika
authors.initials: R
authors.lastname: Puttagunta
authors.affiliation: 1 Laboratory for NeuroRegeneration and Repair, Centre for Neurology, Hertie Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany 4 Molecular Neuroregeneration, Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK s.di-giovanni@imperial.ac.uk.
authors.forename: Simone
authors.initials: S
authors.lastname: Di Giovanni
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology; D019295:Computational Biology; D004195:Disease Models, Animal; D005434:Flow Cytometry; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009409:Nerve Crush; D009416:Nerve Regeneration / Q000502:physiology*; D020221:Optic Nerve Injuries / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D020127:Recovery of Function / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D013119:Spinal Cord Injuries / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D059467:Transcriptome; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: C461497:Mdm4 protein, mouse; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases
keywords: IGF1R; MDM2; MDM4; optic nerve; p53; spinal cord injury, regeneration