Genetic evidence for selectiveneurotrophin3signalling through TrkC but not TrkB in vivo

Neurotrophins control neuronal survival in a target-derived manner during the period of naturally occurring cell death in development. The specificity of this mechanism has been attributed to a restricted spatio-temporal expression of neurotrophin ligands in target tissues, as well as a selective expression of their cognate tyrosine kinase (Trk) receptors in different neuronal subpopulations. However, several in vitro and in vivo studies of null mutant mice have suggested that neurotrophin 3 (NT3) also signals through the non-preferred TrkB receptor. In this study, we have directly addressed the in vivo preference of NT3 to signal through TrkB or TrkC, by crossing the NT3 knock-in mice (BDNFNT3/NT3 mice) with the TrkBor TrkC-null mutant mice. We find that TrkB is dispensable, whereas TrkC is required for the neuronal rescue by the NT3 allele in the brain-derived neurotrophic factorand NT3-dependent cochleovestibular system. Our results show that NT3 maintains survival of cells as well as target innervation only through interactions with TrkC in vivo. TrkB and TrkC receptors are thus not functionally redundant for NT3, even when coexpressed in neurons of the cochleovestibular system.