Downregulation of UBE4B promotes CNS axon regrowth and functional recovery after stroke

The limited intrinsic regrowth capacity of corticospinal axons impedes functional recovery after cortical stroke. Although the mammalian target of rapamycin (mTOR) and p53 pathways have been identified as the key intrinsic pathways regulating CNS axon regrowth, little is known about the key upstream regulatory mechanism by which these two major pathways control CNS axon regrowth. By screening genes that regulate ubiquitin-mediated degradation of the p53 pro-teins in mice, we found that ubiquitination factor E4B (UBE4B) represses axonal regrowth in retinal ganglion cells and corticospinal neurons. We found that axonal regrowth induced by UBE4B depletion depended on the cooperative activation of p53 and mTOR. Importantly, overexpression of UbV.E4B, a competitive inhibitor of UBE4B, in corticospinal neurons promoted corticospinal axon sprouting and facilitated the recovery of corticospinal axon-dependent function in a cortical stroke model. Thus, our findings provide a translatable strategy for restoring corticospinal tract-dependent functions after cortical stroke.

Automated summary

The limited regrowth capacity of corticospinal axons after cortical stroke hinders functional recovery. In this study, we identified ubiquitination factor E4B (UBE4B) as a regulator of axonal regrowth in retinal ganglion cells and corticospinal neurons. UBE4B represses axonal regrowth through the cooperative activation of p53 and mTOR pathways. Overexpression of UbV.E4B, a competitive inhibitor of UBE4B, promotes corticospinal axon sprouting and facilitates recovery of corticospinal tract-dependent function in a cortical stroke model.