Sustained axon regeneration induced by co-deletion of PTEN and SOCS3

Nerve regeneration at a distance Long-range extensive repair following nerve damage has been demonstrated in the peripheral nervous system, but such robust regeneration is rare in the central nervous system. Previous studies have observed some repair following molecular manipulations of the regeneration signalling pathways, but these gains often tapered off after two weeks. Zhigang He and colleagues identify a modification to two signalling pathways that promotes enhanced axonal regeneration following a nerve crush injury. These manipulated pathways act in synergy to promote the expression of growth-related genes that maintain high enough levels to sustain long-range regenerative growth. A formidable challenge in neural repair in the adult central nervous system (CNS) is the long distances that regenerating axons often need to travel in order to reconnect with their targets. Thus, a sustained capacity for axon regeneration is critical for achieving functional restoration. Although deletion of either phosphatase and tensin homologue (PTEN), a negative regulator of mammalian target of rapamycin (mTOR), or suppressor of cytokine signalling 3 (SOCS3), a negative regulator of Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway, in adult retinal ganglion cells (RGCs) individually promoted significant optic nerve regeneration, such regrowth tapered off around 2 weeks after the crush injury 1 , 2 . Here we show that, remarkably, simultaneous deletion of both PTEN and SOCS3 enables robust and sustained axon regeneration. We further show that PTEN and SOCS3 regulate two independent pathways that act synergistically to promote enhanced axon regeneration. Gene expression analyses suggest that double deletion not only results in the induction of many growth-related genes, but also allows RGCs to maintain the expression of a repertoire of genes at the physiological level after injury. Our results reveal concurrent activation of mTOR and STAT3 pathways as key for sustaining long-distance axon regeneration in adult CNS, a crucial step towards functional recovery.