Neurotrophic Factor Function During Ear Development: Expression Changes Define Critical Phases for Neuronal Viability

Neuronal interactions have two fundamentally different purposes: the release of synaptic transmitters conveys information between neurons whereas co-released neurotrophic factors support survival of neurons as well as growth and pruning of their processes. Cell death and pruning numerically adjusts source to target populations. The developing inner ear is an ideal model to investigate the function of one particular set of neurotrophic factors, the neurotrophins and their receptors. Only two (out of four) neurotrophic factors and their receptors are crucial for the survival of inner ear neurons during development: either loss of both neurotrophic factors or their two receptors lead to complete embryonic loss of all inner ear afferents. In contrast, loss of only one receptor or one neurotrophin results in characteristic and topographically restricted loss of neurons and altered innervation of sensory epithelia. For example, mice genetically engineered to be void of the neurotrophic factor BDNF (brain-derived neurotrophic factor) have no innervation of canal cristae and reduced density of innervation of the apex of the cochlea. In contrast, mouse mutants without the neurotrophic factor NT-3 (neurotrophin 3) show loss of spiral ganglion neurons in the basal turn of the cochlea with no obvious effect on vestibular innervation density. Further, mice genetically engineered to misexpress one neurotrophin under the promoter of the other show that in the cochlea, but not in the vestibular system, one ligand can be replaced by the other ligand. The data on the effects of embryonic loss of neurotrophins fit closely to the original neurotrophic theory, demonstrating a simple quantitative relationship of level and place of neurotrophin expression on the viability of neurons and retention of their processes. In contrast, the rich variation of ratios of afferents to hair cells in the ear is not easily reconcilable with the basic assumption of the neurotrophic theory, namely that neurotrophins regulate numerical matching of innervation proportions.