COORDINATED EXPRESSION AND FUNCTION OF NEUROTROPHINS AND THEIR RECEPTORS IN THE RAT INNER-EAR DURING TARGET INNERVATION

We show that trkB and trkC mRNAS, encoding the high-affinity receptor tyrosine kinases for brain-derived neurotrophic factor (BDNF) and neur otrophin-3 (NT-3), respectively, as well as low-affinity nerve growth factor receptor (p75(LNGFR)) mRNA are expressed in the cochleovestibul ar ganglion (CVG) before and during innervation of the target fields. Correspondingly, from preinnervation stages onward, BDNF and NT-3, but neither nerve growth factor (NGF)nor neurotrophin-4(NT-4) mRNAs are e xpressed in the sensory epithelium of the otic vesicle, the peripheral target field of CVG neurons. No neurotrophin transcripts were detecte d by in situ hybridization in the medullary central targets. In explan t cultures, neuritogenesis from both the cochlear and vestibular part of the CVG was promoted by BDNF, while NT-3 evoked neurites mainly fro m the cochlear neurons. Also NT-4 stimulated neurite outgrowth from th e CVG in vitro. In dissociated neuron-enriched cultures, NT-3 and BDNF promoted survival of overlapping subsets of CVG neurons and, correspo ndingly, results from in situ hybridization showed that both trkC and trkB mrnas were expressed in most neurons of this ganglion. The neglig ible effect of NGF seen in the bioassays agrees well with the expressi on of only a few trkA transcripts, encoding the high-affinity receptor for NGF, in the CVG. Based on the spatiotemporal expression patterns and biological effects in vitro, peripherally-synthesized BDNF and NT- 3 regulate the survival of CVG neurons as well as the establishment of neuron-target cell contacts in the early-developing inner ear. In add ition, the expression of trkB mRNA, more specifically its truncated fo rm, and trkC as well as p75(LNGFR) mRNAS in distinct, non-neuronal str uctures indicates novel roles for these molecules during development.