Targeting Retinoblastoma Protein Offers Therapeutic Opportunities For Peripheral Nerve Injury

Abstract

Peripheral nerve injury is common. Severed peripheral axons that fail to reconnect to their targets are associated with temporary or permanent functional impairment. Fortunately, the higher intrinsic capacity of axons in the PNS to regrow compared with their counterparts in the CNS justifies exploring strategies to ramp up effi cient regeneration. Peripheral nerve injury, or axotomy, triggers a cascade of events: a degenerative phase that involves breakdown of axons and myelin within the distal stump, dying back of axons in the proximal stump up to the first node of Ranvier, clearance of myelin debris by Schwann cells (SCs) and macrophages, a regenerative phase involving upregulation of regeneration-associated genes in neurons and SCs, reconstruction of the endoneurial assembly including repopulation of cytoskeletol molecules in axons and finally reconnec tion to targets [1]. Unfortunately, the active regenerative phase is circumscribed, peaking at 7 days postaxotomy whereas failure to generate an effective regenerative milieu within this span of time may leave behind the axons with poor regenerative and sprouting capacity. Misdirected growth of axons to nonspecific targets also compli cates successful regrowth. Therapies aimed at inactivating the inhibitory molecules that dampen the intrinsic growth response of neurons within the microenvironment may be an efficient and feasible strategy to improve regeneration in the PNS. For example, targeting the inhibitory molecule RHOA has a striking impact in enhancing the regenerative capacity of peripheral axons [2]. Tumor suppressors are a class of molecules possessing growth inhibitory properties. Their presence in the injured nerves can be compared with deracinated trees, in the path of axon regeneration, with numerous and divergent signaling branches targeted for growth inhibition. Relieving the growth inhibition posed by such inhibitors, for example, targeting the central growth ‘brake’ PTEN, has proven remarkably effective in increasing the extent by which peripheral axons regenerate [3]. Having experience with this approach in our laboratory, we have recently identified another tumor suppressor, retinoblastoma protein (Rb1), as a novel target for improving PNS regeneration [4].