NT-3 Replacement with Brain-Derived Neurotrophic Factor Redirects Vestibular Nerve Fibers to the Cochlea

Abstract

Survival of inner ear sensory neurons depends on two neurotrophins, BDNF and NT-3, and their respective receptors, TrkB and TrkC. Because both receptors are present in the same neuron, it has been suggested that BDNF and NT-3 are functionally redundant in promoting neuronal survival. Knock-in of one ligand into the locus of the other one confirmed this hypothesis for the cochlea, leaving open the question of why two neurotrophins are required for proper innervation of the mammalian ear. Here, we show that the precise spatiotemporal pattern of expression of the two neurotrophins is essential for proper patterning of the inner ear innervation. Mice expressing BDNF under the control of the NT-3 promoter develop exuberant projections of vestibular sensory neurons to the basal turn of the cochlea. This projection can be enhanced by combining the transgene with a null mutation of BDNF. However, vestibular fibers rerouted into the cochlea do not reach hair cells and remain outside the organ of Corti, suggesting a chemotactic role for neurotrophins on these fibers. Our data provide genetic evidence that neurotrophins in the ear exert both survival and axon guidance roles.