NEUROTROPHIN-4 IS A TARGET-DERIVED NEUROTROPHIC FACTOR FOR NEURONS OFTHE TRIGEMINAL GANGLION

The cellular localization of mRNA for neurotrophin-4 (NT-4), a novel n eurotrophic factor, in the developing whisker follicles and skin of th e embryonic rat is demonstrated by in situ hybridization. Levels of NT -4 mRNA in the whisker pad decrease between embryonic day 13 (E13) and E20, correlating in time with the onset of naturally occurring neuron al death in the innervating trigeminal ganglion. In addition to NT-4, brain-derived neuotrophic factor (BDNF) mRNA is also shown to be expre ssed in the rat embryonic whisker follicles although in a different ce llular localization, which combined with previous data on the expressi on of NGF and NT-3 mRNAs, shows that all four neurotrophins are expres sed during development of this structure. NT-4 protein is shown to eli cit neurite outgrowth from explanted embryonic trigeminal ganglia and to promote neuronal survival of dissociated trigeminal ganglion neuron s when cultured during the phase of cell death. NT-4 and NT-3 mainly s upport different neuronal subpopulations, whereas some NT-4-responsive cells appear to respond also to NGF and BDNF. Analysis of mRNAs for m embers of the Trk family of neurotrophin receptors in neurons rescued by different neurotrophins demonstrates the presence of distinct neuro nal subpopulations that respond to specific combinations of these fact ors. Based on these results we propose that NT-4, together with the ot her three neurotrophins, orchestrate the innervation of the different structures of the developing whisker pad by the trigeminal ganglion, a cting as target-derived neurotrophic factors for different subpopulati ons of trigeminal ganglion neurons.