The development of the peripheral nervous system is governed in part by a f
amily of neurotrophic factors that signal through Trk tyrosine kinase recep
tors. Neurotrophin 3 (NT3) ablation in mice causes a more severe neuronal p
henotype than deletion of its receptor TrkC, suggesting that NT3 acts also
through other non-preferred Trk receptors. To study the role of low-affinit
y ligand receptor interactions in vivo, we have replaced the Nt3 gene with
the gene for brain-derived neurotrophic factor (BDNF), a TrkB ligand. As in
NT3 and TrkC null mice, the proprioception system of these mutants failed
to assemble. However, sensory fiber projections in the embryonic spinal cor
d suggest chemotropic effects of BDNF in vivo. In the dorsal root ganglia,
the developmental dynamic of neuron numbers demonstrates that NT3 is requir
ed for activation of TrkB during neurogenesis and that TrkA is required dur
ing target tissue innervation. In the inner ear, the ectopic BDNF rescued t
he severe neuronal deficits caused by NT3 absence, indicating that TrkB and
TrkC activate equivalent pathways to promote survival of cochlear neurons.
However, specific increased innervation densities suggest unique functions
for BDNF and NT3 beyond promoting neuronal survival. This mouse model has
allowed the dissection of specific spatiotemporal Trk receptor activation b
y NT3. Our analysis provides examples of how development can be orchestrate
d by complex high- and low-affinity interactions between ligand and recepto
r families.