Spatial shaping of cochlear innervation by temporally regulated neurotrophin expression

Previous work suggested qualitatively different effects of neurotrophin 3 ( NT-3) in cochlear innervation patterning in different null mutants. We now show that all NT-3 null mutants have a similar phenotype and lose all neuro ns in the basal turn of the cochlea. To understand these longitudinal defic its in neurotrophin mutants, we have compared the development of the defici t in the NT-3 mutant to the spatial-temporal expression patterns of brain-d erived neurotrophic factor (BDNF) and NT-3, using lacZ reporters in each ge ne and with expression of the specific neurotrophin receptors, trkB and trk C. In the NT-3 mutant, almost normal numbers of spiral ganglion neurons for m, but fiber outgrowth to the basal turn is eliminated by embryonic day (E) 13.5. Most neurons are lost between E13.5 and E15.5. During the period pre ceding apoptosis, NT-3 is expressed in supporting cells, whereas BDNF is ex pressed mainly in hair cells, which become postmitotic in an apical to basa l temporal gradient. During the period of neuronal loss, BDNF is absent fro m the basal cochlea, accounting for the complete loss of basal turn neurons in the NT-3 mutant. The spatial gradients of neuronal loss in these two mu tants appear attributable to spatial-temporal gradients of neurotrophin exp ression. Our immunocytochemical data show equal expression of their recepto rs, TrkB and TrkC, in spiral sensory neurons and thus do not relate to the basal turn loss. Mice in which NT-3 was replaced by BDNF show a qualitative normal pattern of innervation at E13.5. This suggests that the pattern of expression of neurotrophins rather than their receptors is essential for th e spatial loss of spiral sensory neurons in NT-3 null mutants.