Developing vestibular ganglion neurons switch trophic sensitivity from BDNF to GDNF after target innervation.

Recent evidence showing a distinctive cell loss in vestibular and cochlear ganglia of brain-derived neurotrophic factor (BDNF) versus neurotrophin-3 (NT-3) null mutant mice demonstrates that these neurotrophins play a critical role in inner ear development. In this study, biological functions of BDNF and NT-3 in the chick vestibular and cochlear ganglion development was assessed in vitro and compared to those of other neurotrophic factors. The embryonic day (E)8-12 vestibular ganglion neurons showed an extensive outgrowth in response to BDNF with less outgrowth to NT-3. In contrast, NT-3 had stronger neurotrophic effects on the E12 cochlear ganglion neurons compared to BDNF. These results support previous evidence that neurotrophins play important roles in the vestibular and cochlear ganglion neuron development. However, the responsiveness to the neurotrophins declined and became undetectable by E16. Unexpectedly, glial cell line-derived neurotrophic factor (GDNF) promoted neurite outgrowth from vestibular ganglia at E12-16, later than the stages at which BDNF had neurotrophic effects. The time of switching sensitivity of the vestibular ganglion neurons from BDNF to GDNF correlated with the time of completion of synaptogenesis on their peripheral and central targets. Furthermore, a factor released from E12 inner ears exerted neurotrophic effects on late-stage vestibular ganglion neurons that were not responsive to the E4 otocyst-derived factor. These results raise the possibility that the vestibular ganglion neurons become responsive to GDNF upon target innervation and that the changes in sensitivity are regulated by changes in available factors released from their peripheral targets, the inner ear epithelia.

Developmental changes in growth factors released by the embryonic inner ear.

Recent studies have demonstrated a role for neurotrophins in regulating the survival of developing auditory and vestibular neurons. However, the developmental time-course for neurotrophin production and release by inner ear tissues has not been defined. In the present study, neurotrophin-like activity was evaluated from culture medium conditioned by early- or midembryonic stage inner ears. Examination of the proteinaceous properties of conditioned medium revealed a developmental change in growth factor release by the inner ear. Neurotrophin-like molecules were not detected in medium conditioned by early stage otocysts. In contrast, neurotrophin-like bioactivity was detected in medium conditioned by middevelopmental stage inner ears. Western blot analysis revealed that NT-3 was released by the rat inner ear at midstages of inner ear development. ELISA measurements revealed that both NT-3 and BDNF are produced by the middevelopmental stage inner ear, and that NT-3 protein levels are higher than BDNF levels. These results suggest that there are developmental changes in the release of growth factors by the inner ear.