Dissection of NT3 functions in vivo by gene replacement strategy.
The development of the peripheral nervous system is governed in part by a family of neurotrophic factors that signal through Trk tyrosine kinase receptors. Neurotrophin 3 (NT3) ablation in mice causes a more severe neuronal phenotype than deletion of its receptor TrkC, suggesting that NT3 acts also through other non-preferred Trk receptors. To study the role of low-affinity 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 cord suggest chemotropic effects of BDNF in vivo. In the dorsal root ganglia, the developmental dynamic of neuron numbers demonstrates that NT3 is required for activation of TrkB during neurogenesis and that TrkA is required during target tissue innervation. In the inner ear, the ectopic BDNF rescued the 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 by NT3. Our analysis provides examples of how development can be orchestrated by complex high- and low-affinity interactions between ligand and receptor families.
Coppola
V
V
Neural Development Group, Mouse Cancer Genetics Program, NCI, Frederick, MD 21701, USA.
Kucera
J
J
Palko
M E
ME
Martinez-De Velasco
J
J
Lyons
W E
WE
Fritzsch
B
B
Tessarollo
L
L
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D007758:Ear, Inner / Q000196:embryology / Q000294:innervation; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology / Q000196:embryology*; D005821:Genetic Techniques; D051379:Mice; D008817:Mice, Mutant Strains; D009475:Neurons, Afferent / Q000378:metabolism / Q000473:pathology; D020933:Neurotrophin 3 / Q000502:physiology*; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism; D020812:Receptor, trkC / Q000235:genetics / Q000378:metabolism; D013116:Spinal Cord / Q000166:cytology / Q000196:embryology
D019208:Brain-Derived Neurotrophic Factor; D020933:Neurotrophin 3; D020813:Receptor, trkB; D020812:Receptor, trkC