Selective regulation of trkC expression by NT3 in the developing peripheral nervous system

Abstract

We have studied the influence of neurotrophin-3 (NT3) on the expression of its receptor tyrosine kinase, trkC, in embryonic mice. The expression of trkC transcripts encoding full-length and kinase-deficient receptors was almost entirely restricted to neurons in the trigeminal ganglion and increased markedly throughout development. In NT3(+/-) embryos, the level of trkC mRNA in the trigeminal ganglion was much lower than that in wild-type embryos, although there was no significant reduction in the total number of neurons in the ganglion. This demonstrates that endogenous NT3 regulates trkC expression in trigeminal neurons independently of changes in population size. In NT3(-/-) embryos, the number of neurons in the trigeminal ganglion was much lower than in wild-type embryos, and there was a further reduction in the mean neuronal level of trkC mRNA. Direct regulation of trkC mRNA expression in cultured trigeminal neurons was also observed, although the finding that trkC mRNA levels were sustained better in explant cultures than in dissociated cultures irrespective of the presence of NT3 suggests that trkC mRNA expression is regulated by additional factors within the ganglion. In contrast to trigeminal neurons, the level of trkC mRNA was sustained at normal levels in neurons of the sympathetic chain of NT3(-/-) embryos and was not increased by NT3 in sympathetic neuron-cultures. TrkC mRNA expression in developing cutaneous tissues was also unaffected by the NT3 null mutation. In summary, our findings provide the first clear evidence that the expression of a trk receptor, tyrosine kinase, is regulated by physiological levels of its ligand in vivo and show that regulation by NT3 is cell type-specific.