Neurotrophin-4/5 is required for the early growth of regenerating axons in peripheral nerves.

The requirement of the trkB ligand, neurotrophin-4/5 (NT-4/5), for the growth of regenerating axons in the peripheral nervous system (PNS) is not well established. We studied regenerating axon growth in transected peripheral nerves of thy-1-YFP-H mice that had been repaired using allografts obtained from brain-derived neurotrophic factor (BDNF) or NT-4/5 knockout mice. Lengths of profiles of YFP+ axons measured in these grafts were compared with those measured in grafts obtained from wild-type donors. When compared with axon profiles measured in grafts from wild-type donors, axon profile lengths measured in grafts from homozygous (NT-4/5(-/-)) or heterozygous (NT-4/5(+/-)) mice were significantly shorter. In contrast, the lengths of axon profiles measured in grafts from BDNF(+/-) mice were not significantly different from those measured in grafts from wild-type mice. A reduced amount of BDNF, but not NT-4/5, is sufficient to promote the elongation of regenerating axons in the PNS. When grafts from wild-type or NT-4/5(-/-) mice were treated acutely at the time of surgical repair either with exogenous BDNF or NT-4/5, the lengths of axon profiles measured in the grafts were significantly longer than those measured in grafts from untreated wild-type mice. These findings are consistent with a requirement for NT-4/5 from within the pathway used by regenerating axons for the successful growth of those axons in peripheral nerves.