SYNCHRONOUS ONSET OF NGF AND TRKA SURVIVAL DEPENDENCE IN DEVELOPING DORSAL-ROOT GANGLIA

Determinations of dorsal root ganglion (DRG) neuron loss in nerve grow th factor (NGF) and neurotrophin-3 (NT-3) null mutant mice have suppor ted the concept that neurons can switch neurotrophin dependence by rev ealing that many neurons must require both of these factors acting eit her sequentially or simultaneously during development. The situation i s complex, however, in that NT-3(-/-) mutant mice show far greater neu ron loss than mice deficient in the NT-3 receptor TrkC, suggesting tha t NT-3 may support many DRG neurons via actions on the NGF receptor Tr kA. To assess the possibility of ligand-receptor cross-talk as a devel opmental mechanism, we have compared the onset of survival dependence of lumbar DRG neurons on NT-3, TrkC, NGF, and TrkA signaling in mice d eficient in these molecules as a result of gene targeting. At embryoni c day 11.5 (E11.5), virtually all lumbar DRG cells express TrkC mRNA a nd many require NT-3 and TrkC signaling for survival. In contrast, alt hough many lumbar DRG cells also express TrkA at E11.5, there is littl e survival dependence on TrkA signaling. By E13.5, most lumbar DRG cel ls have downregulated TrkC mRNA. The onset of survival dependence on N GF and TrkA-signaling is concurrent and of equal magnitude at E13.5, d emonstrating that NT-3 alone does not support DRG neurons via TrkA, no r can NT-3 compensate for the loss of NGF, We conclude that many murin e DRG cells require NT-3 for survival before exhibiting NGF dependence and that NT-3 activation of TrkA is unimportant to these early NT-3 s urvival-promoting actions. We suggest that the discrepancy in cell los s between NT-3(-/-) and trkC(-/-) mutants is attributable to the abili ty of NT-3 to support DRG neurons via TrkA in the artificial situation where TrkC is absent.