The MDM4/MDM2-p53-IGF1 axis controls axonal regeneration, sprouting and functional recovery after CNS injury
File(s)
Accepted version
Author(s)
Type
Journal Article
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.
Date Issued
2015-05-28
Date Acceptance
2015-03-09
Citation
Brain, 2015, 138 (7), pp.1843-1862
ISSN
0006-8950
Publisher
Oxford University Press (OUP)
Start Page
1843
End Page
1862
Journal / Book Title
Brain
Volume
138
Issue
7
Copyright Statement
This is a pre-copyedited, author-produced PDF of an article accepted for publication in Brain following peer review. The version of record Yashashree Joshi, Marília Grando Sória, Giorgia Quadrato, Gizem Inak, Luming Zhou, Arnau Hervera, Khizr I. Rathore, Mohamed Elnaggar, Magali Cucchiarini, Jeanne Christophe Marine, Radhika Puttagunta, Simone Di Giovanni. The MDM4/MDM2-p53-IGF1 axis controls axonal regeneration, sprouting and functional recovery after CNS injury. Brain 138:77, pp. 1843-1862 First published online: 16 May 2015 is available online at: https://dx.doi.org/10.1093/brain/awv125
Sponsor
Wings for Life Spinal Cord Research Foundation
International Spinal Research Trust
Grant Number
WFL-GB-021/13
NRB111
Subjects
Science & Technology
Life Sciences & Biomedicine
Clinical Neurology
Neurosciences
Neurosciences & Neurology
MDM4
MDM2
IGF1R
p53
optic nerve
spinal cord injury
regeneration
SPINAL-CORD-INJURY
GROWTH CONE COLLAPSE
CORTICOSPINAL TRACT
NEURITE OUTGROWTH
FAMILY-MEMBERS
OPTIC-NERVE
P53 PATHWAY
ADULT CNS
IN-VIVO
ACTIVATION
Publication Status
Published