Imperial College London
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ProfessorSimoneDi Giovanni

Faculty of Medicine, Department of Brain Sciences

James W Harnett Chair in Restorative Neuroscience
 
 
 
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Contact

 

+44 (0)20 7594 3178s.di-giovanni

 
 
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Location

 

E505Burlington DanesHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Joshi:2015:brain/awv125,
author = {Joshi, Y and Soria, MG and Quadrato, G and Inak, G and Zhou, L and Hervera, A and Rathore, KI and Elnaggar, M and Magali, C and Marine, JC and Puttagunta, R and Di, Giovanni S},
doi = {brain/awv125},
journal = {Brain},
pages = {1843--1862},
title = {The MDM4/MDM2-p53-IGF1 axis controls axonal regeneration, sprouting and functional recovery after CNS injury},
url = {http://dx.doi.org/10.1093/brain/awv125},
volume = {138},
year = {2015}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
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.
AU  - Joshi,Y
AU  - Soria,MG
AU  - Quadrato,G
AU  - Inak,G
AU  - Zhou,L
AU  - Hervera,A
AU  - Rathore,KI
AU  - Elnaggar,M
AU  - Magali,C
AU  - Marine,JC
AU  - Puttagunta,R
AU  - Di,Giovanni S
DO  - brain/awv125
EP  - 1862
PY  - 2015///
SN  - 0006-8950
SP  - 1843
TI  - The MDM4/MDM2-p53-IGF1 axis controls axonal regeneration, sprouting and functional recovery after CNS injury
T2  - Brain
UR  - http://dx.doi.org/10.1093/brain/awv125
UR  - http://hdl.handle.net/10044/1/31835
VL  - 138
ER  -
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