TY  - JOUR
AU  - Joshi, Yashashree
AU  - Sória, Marília Grando
AU  - Quadrato, Giorgia
AU  - Inak, Gizem
AU  - Zhou, Luming
AU  - Hervera, Arnau
AU  - Rathore, Khizr I
AU  - Elnaggar, Mohamed
AU  - Cucchiarini, Magali
AU  - Magali, Cucchiarini
AU  - Marine, Jeanne Christophe
AU  - Puttagunta, Radhika
AU  - Di Giovanni, Simone
TI  - The MDM4/MDM2-p53-IGF1 axis controls axonal regeneration, sprouting and functional recovery after CNS injury.
JO  - Brain
VL  - 138
IS  - 7
SN  - 0006-8950
CY  - Oxford
PB  - Oxford Univ. Press
M1  - DZNE-2020-04358
SP  - 1843-1862
PY  - 2015
AB  - 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.
KW  - Animals
KW  - Axons: metabolism
KW  - Axons: pathology
KW  - Computational Biology
KW  - Disease Models, Animal
KW  - Flow Cytometry
KW  - Immunoblotting
KW  - Immunohistochemistry
KW  - Immunoprecipitation
KW  - Insulin-Like Growth Factor I: metabolism
KW  - Mice
KW  - Mice, Inbred C57BL
KW  - Mice, Mutant Strains
KW  - Nerve Crush
KW  - Nerve Regeneration: physiology
KW  - Optic Nerve Injuries: metabolism
KW  - Optic Nerve Injuries: pathology
KW  - Optic Nerve Injuries: physiopathology
KW  - Proto-Oncogene Proteins: metabolism
KW  - Proto-Oncogene Proteins c-mdm2: metabolism
KW  - Recovery of Function: physiology
KW  - Reverse Transcriptase Polymerase Chain Reaction
KW  - Signal Transduction: physiology
KW  - Spinal Cord Injuries: metabolism
KW  - Spinal Cord Injuries: pathology
KW  - Spinal Cord Injuries: physiopathology
KW  - Transcriptome
KW  - Tumor Suppressor Protein p53: metabolism
KW  - Ubiquitin-Protein Ligases: metabolism
KW  - Mdm4 protein, mouse (NLM Chemicals)
KW  - Proto-Oncogene Proteins (NLM Chemicals)
KW  - Tumor Suppressor Protein p53 (NLM Chemicals)
KW  - insulin-like growth factor-1, mouse (NLM Chemicals)
KW  - Insulin-Like Growth Factor I (NLM Chemicals)
KW  - Mdm2 protein, mouse (NLM Chemicals)
KW  - Proto-Oncogene Proteins c-mdm2 (NLM Chemicals)
KW  - Ubiquitin-Protein Ligases (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:25981963
DO  - DOI:10.1093/brain/awv125
UR  - https://pub.dzne.de/record/138036
ER  -