TARGETED EXPRESSION OF A MULTIFUNCTIONAL CHIMERIC NEUROTROPHIN IN THELESIONED SCIATIC-NERVE ACCELERATES REGENERATION OF SENSORY AND MOTOR AXONS

Peripheral nerve injury markedly regulates expression of neurotrophins and their receptors in the lesioned nerve. However, the role of endog enously produced neurotrophins in the process of nerve regeneration is unclear. Expression of a multifunctional neurotrophin, pan-neurotroph in-1 (PNT-1), was targeted to the peripheral nerves of transgenic mice by using a gene promoter that is specifically activated after nerve l esion but that is otherwise silent in all other tissues and during dev elopment. PNT-1 is a chimeric neurotrophin that combines the active si tes of the neurotrophins nerve growth factor, brain derived neurotroph ic factor, and neurotrophin-3 and binds and activates all known neurot rophin receptors, In adult transgenic mice, PNT-1 was highly expressed in transected but not in intact sciatic nerve. Morphometric analyses at the electron microscopy level showed increased and accelerated reco very of axon diameter of myelinated fibers in crushed peripheral nerve s of transgenic mice compared with wild type. Examination of nerve bun dles in target tissues indicated accelerated reinnervation of foot pad dermis and flexor plantaris muscle in transgenic mice. Moreover, tran sected sensory and motor axons of transgenic mice showed faster and in creased return of neurophysiological responses, suggesting an accelera ted rate of axonal elongation. Importantly, transgenic mice also showe d a markedly ameliorated loss of skeletal muscle weight, indicating fu nctional regeneration of motor axons. Together, these data provide evi dence, at both the anatomical and functional levels, that neurotrophin s endogenously produced by the lesioned nerve are capable of significa ntly accelerating the regeneration of both sensory and motor axons aft er peripheral nerve damage. In addition, our results indicate that exo genous PNT-1 administration may be an effective therapeutic treatment of peripheral nerve injuries.