The MDM4/MDM2-p53-IGF1 axis controls axonal regeneration, sprouting and functional recovery after CNS injury

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.

Targeting MDM2 for novel molecular therapy: Beyond oncology

“…They have observed that both MDMX deletion and MDM2 inhibition by nutlin‐3a enabled nerve regeneration after optic nerve crush or spinal cord injury . A genome‐wide gene expression analysis has indicated that IGF1R is a downstream effector of MDMX deletion, and the activity and expression of IGF1R are necessary for regeneration . These results suggest that the MDM2/MDMX‐p53‐IGF1 signaling axis contributes to axonal regrowth and functional recovery after CNS injury, and may be a promising target for improving axonal regeneration and neurological recovery.…”

“…Joshi et al have demonstrated that MDM2 and MDMX limit axonal regeneration in the central nervous system (CNS), particularly in the injured optic nerve, by regulating the p53‐insulin‐like growth factor 1 (p53‐IGF1) axis (Table ) . They have observed that both MDMX deletion and MDM2 inhibition by nutlin‐3a enabled nerve regeneration after optic nerve crush or spinal cord injury . A genome‐wide gene expression analysis has indicated that IGF1R is a downstream effector of MDMX deletion, and the activity and expression of IGF1R are necessary for regeneration .…”

p53 on the crossroad between regeneration and cancer

“…Accordingly, inhibition of the triad or one of its components promoted functional recovery after spinal cord injury. 67 …”

Combinatorial proteomics and transcriptomics identify AMPK in the control of the axonal regeneration programme of DRG sensory neurons after spinal injury

“…Additionally, GSK3β, whose downregulation stimulates axonal regeneration of sensory neurons 74 , inhibits the mTOR pathway by phosphorylating TSC2 in a manner dependent on AMPK-priming phosphorylation 73 . Interestingly, IGF1 signalling, recently shown to promote axonal regeneration by others and us 75,76 , is inhibited by AMPK activation 77 .…”