Brain-derived neurotrophic factor is required for normal peripheral nerve development and regeneration

Brain-derived neurotrophic factor (BDNF) is dynamically expressed in peripheral nerve during development and again during regeneration. BDNF null mice suffer perinatal lethality preventing the study of the adult functions of BDNF. Mice lacking BDNF in their Schwann cells were generated using Cre/lox technology to analyze BDNF requirements in developing and regenerating nerve. Transgenic mice expressing Cre recombinase under the control of the P0 promoter were bred with mice having the BDNF coding exon flanked by lox sites to generate Schwann cells-specific knockouts (P0cre-BDNFKO). These mice were viable and survived well into adulthood but expressed reduced levels of BDNF protein in peripheral nerve and the normal increase in BDNF that occurs after a nerve injury was not apparent. P0cre-BDNF KO mice had delayed functional recovery 2 weeks after a sciatic nerve crush injury which correlated with the presence of fewer regenerated myelinated axons at that time point. Interestingly, axons of all sizes in the P0cre-BDNFKO mice were hypermyelinated both in uninjured and regenerating states. Non-circularity of myelinated axons was also increased in P0cre-BDNFKO mice, however, myelin sheath ultrastructure and organization appeared normal. No effects were observed on non-myelinated axon density, size or distribution. Thus, BDNF is needed for normal regeneration and for a normal rate of nerve regeneration after injury. Moreover, the results of this study argue that the functions of BDNF in peripheral nerve may be more complex than previously described. BDNF produced by Schwann cells and peripheral nerve axons could have distinct and sometimes opposing functions in development and regeneration. A model to explain the various roles of BDNF in peripheral nerve is proposed.