DIFFERENTIAL-EFFECTS OF COMBINED TRK RECEPTOR MUTATIONS ON DORSAL-ROOT GANGLION AND INNER-EAR SENSORY NEURONS

We have generated double mutant mice deficient in pairs of two differe nt Trk receptors and have analysed the effects on survival and differe ntiation of dorsal root ganglion (DRG), inner ear cochlear and vestibu lar sensory neurons, In most combinations of mutant trk alleles, the d efects observed in double compared to single mutant mice were additive . However, double homozygous trkA(-/-);trkB(-/-)DRG and trkB(-/-);trkC (-/-) vestibular neurons showed the same degree of survival as single trkA(-/-) and trkB(-/-) mice, respectively, suggesting that those neur ons required both Trk signaling pathways for survival, In situ hybridi sation analysis of DRG neurons of double mutant mice revealed differen tial expression of excitatory neuropeptides. Whereas calcitonin-gene-r elated peptide expression correlated with the trkA phenotype, substanc e P expression was detected in all combinations of double mutant mice. In the inner ear, TrkB- and TrkC-dependent neurons were shown to at l east partially depend on each other for survival, most likely indirect ly due to abnormal development of their common targets. This effect wa s not observed in DRGs, where neurons depending on different Trk recep tors generally innervate different targets.