MDM4/MDM2-p53-IGF1R in nerve regeneration of the CNS

Professor Simone di Giovanni Imperial College of London

Professor Simone di Giovanni Imperial College of London

I had reported on May 31st in a blog post about the effects of the Nutlins cancer drug, but here is a video that may better explain what is happening with this research. MDM4/MDM2-p53-IGF1R in CNS nerve regeneration is explained by Professor Simone di Giovanni, Imperial College London

Ubiquitin ligases coordinate neuronal morphogenesis and connectivity during development and after axonal injury. Joshi et al. show that the ubiquitin ligases MDM4-MDM2 interact with p53 to regulate IGF1R signalling, and that modulation of this pathway enhances axonal regeneration and functional recovery after visual system or spinal cord injury.

BRAIN OXFORD JOURNAL ABSTRACT: The MDM4/MDM2-p53-IGF1 axis controls axonal regeneration, sprouting and functional recovery after CNS injury

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 signaling 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 supra-spinal 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.


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