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@ARTICLE{Joshi:138036,
      author       = {Joshi, Yashashree and Sória, Marília Grando and Quadrato,
                      Giorgia and Inak, Gizem and Zhou, Luming and Hervera, Arnau
                      and Rathore, Khizr I and Elnaggar, Mohamed and Cucchiarini,
                      Magali and Magali, Cucchiarini and Marine, Jeanne Christophe
                      and Puttagunta, Radhika and Di Giovanni, Simone},
      title        = {{T}he {MDM}4/{MDM}2-p53-{IGF}1 axis controls axonal
                      regeneration, sprouting and functional recovery after {CNS}
                      injury.},
      journal      = {Brain},
      volume       = {138},
      number       = {7},
      issn         = {0006-8950},
      address      = {Oxford},
      publisher    = {Oxford Univ. Press},
      reportid     = {DZNE-2020-04358},
      pages        = {1843-1862},
      year         = {2015},
      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
                      $recovery.media-1vid110.1093/brain/awv125_video_abstractawv125_video_abstract.$},
      keywords     = {Animals / Axons: metabolism / Axons: pathology /
                      Computational Biology / Disease Models, Animal / Flow
                      Cytometry / Immunoblotting / Immunohistochemistry /
                      Immunoprecipitation / Insulin-Like Growth Factor I:
                      metabolism / Mice / Mice, Inbred C57BL / Mice, Mutant
                      Strains / Nerve Crush / Nerve Regeneration: physiology /
                      Optic Nerve Injuries: metabolism / Optic Nerve Injuries:
                      pathology / Optic Nerve Injuries: physiopathology /
                      Proto-Oncogene Proteins: metabolism / Proto-Oncogene
                      Proteins c-mdm2: metabolism / Recovery of Function:
                      physiology / Reverse Transcriptase Polymerase Chain Reaction
                      / Signal Transduction: physiology / Spinal Cord Injuries:
                      metabolism / Spinal Cord Injuries: pathology / Spinal Cord
                      Injuries: physiopathology / Transcriptome / Tumor Suppressor
                      Protein p53: metabolism / Ubiquitin-Protein Ligases:
                      metabolism / Mdm4 protein, mouse (NLM Chemicals) /
                      Proto-Oncogene Proteins (NLM Chemicals) / Tumor Suppressor
                      Protein p53 (NLM Chemicals) / insulin-like growth factor-1,
                      mouse (NLM Chemicals) / Insulin-Like Growth Factor I (NLM
                      Chemicals) / Mdm2 protein, mouse (NLM Chemicals) /
                      Proto-Oncogene Proteins c-mdm2 (NLM Chemicals) /
                      Ubiquitin-Protein Ligases (NLM Chemicals)},
      cin          = {AG N.N. 3},
      ddc          = {610},
      cid          = {I:(DE-2719)1240015},
      pnm          = {344 - Clinical and Health Care Research (POF3-344)},
      pid          = {G:(DE-HGF)POF3-344},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:25981963},
      doi          = {10.1093/brain/awv125},
      url          = {https://pub.dzne.de/record/138036},
}