Tumor suppressors as critical regulators of the peripheral nerve regenerative milieu

Abstract:

Peripheral nerves are essential connections between the body, brain and spinal cord. Without them, there is no movement or sensation. Damage to peripheral nerves, through major accidents, sports injuries, etc, is common but the disability they render is often devastating. Most importantly, managing a nerve injury is often problematic for its unacceptably slow growth rate and impaired directionality. Currently no effective treatments are in place for complete restoration of damaged nerves and functional recovery. A clear understanding on the intrinsic barriers of nerve growth may offer therapeutic strategies for facilitating peripheral nerve regeneration. We identified that manipulating molecular pathways involved in tumorigenesis, nonetheless expressed in neurons, offer this possibility. We found that selective manipulation of the tumor suppressor proteins Rb1 (Retinoblastoma 1) or BRCA1 (breast cancer susceptibility gene 1) modify the regenerating behavior of injured rodent sciatic nerve. Knockdown of Rb1 was associated with dramatic rises in axon (basic unit of a nerve) outgrowth and partial functional recovery after nerve injury, through mechanisms dependent and independent of its classical E2F pathway, revealing Rb1 as an ideal target for improving peripheral nerve regeneration. In contrast, nuclear localization of BRCA1 has appeared to be highly essential for facilitating nerve regeneration. Our studies suggest that nerve regeneration accompanies with reprogramming of neuronal nuclei for which the nuclear functions of BRCA1 may play a major role. Overall though molecularly distinct, the tumor suppressor pathways associated with Rb1 and BRCA1 modify plasticity of regenerating neurons, a critical advantage for exploring therapeutic intervention points in peripheral nerve injury.