Inhibition of the NT-3 receptor TrkC, early in chick embryogenesis, results in severe reductions in multiple neuronal subpopulations in the dorsal root ganglia.
To assess functions of neurotrophins at defined times in development, we have prepared antibodies of the extracellular domains of each of the trk receptors. Here, antibodies to trkC, the major receptor for NT-3, are used to examine trkC expression and function during the formation and maturation of the chick dorsal root ganglion (DRG). Our results show that in the immature DRG, the majority of cells express trkC, and inhibition of trkC activation results in reductions in neuronal numbers before the period of target-mediated cell death, the time when neurotrophins previously have been shown to regulate survival. Furthermore, blockade of trkC in ovo induced reductions in subpopulations of DRG neurons known to be dependent on NGF, in addition to those dependent on NT-3 during the target-regulated cell death period. An early function for NT-3 on immature DRG neurons is supported further by data presented here that demonstrate that whereas BDNF and NGF can support a subset of immature DRG neurons in vitro, activation of the trkC receptor either by NT-3 binding or via antibody-mediated cross-linking induces the most robust survival response. When all three neurotrophins are combined, the number of surviving neurons does not exceed that supported by NT-3 alone. Together, these data are consistent with coexpression of more than one trk receptor family member on immature sensory neurons, and they demonstrate that inhibition of trkC activation has surprisingly early and pleiotrophic effects on the development of spinal sensory ganglia.
Lefcort
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F
Howard Hughes Medical Institute, Department of Physiology, University of California, San Francisco 94143-0724, USA.
Clary
D O
DO
Rusoff
A C
AC
Reichardt
L F
LF
D000818:Animals; D000918:Antibody Specificity; D017209:Apoptosis / Q000502:physiology; D001483:Base Sequence; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured / Q000737:chemistry / Q000166:cytology; D002642:Chick Embryo; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology / Q000196:embryology* / Q000276:immunology; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology; D007074:Immunoglobulin G / Q000494:pharmacology; D008845:Microinjections; D008969:Molecular Sequence Data; D009414:Nerve Growth Factors / Q000502:physiology; D009474:Neurons / Q000737:chemistry* / Q000166:cytology; D020933:Neurotrophin 3; D010063:Ovum / Q000737:chemistry / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000276:immunology; D020812:Receptor, trkC; D017475:Receptors, Nerve Growth Factor / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000276:immunology
D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D009414:Nerve Growth Factors; D020933:Neurotrophin 3; D017475:Receptors, Nerve Growth Factor; D020794:Receptor Protein-Tyrosine Kinases; D020812:Receptor, trkC