It is widely accepted that many aspects of CNS development are molded by events which occur in the sensory periphery and which are transmitted centrally. For the mammalian nervous system, such information transfer is epitomized by the influence of the rodent whisker field on the patterning of cell groups along the trigeminal neuraxis. To understand the events which are critical for such periphery-to-center relationships to unfold, it is imperative to gain a clear understanding of how the nervous system gets wired up with the periphery. The PI proposes to do this for the trigeminal system, focusing on the role of the neurotrophins (NTs) NGF, BDNF, NT-3, and NT-4 in the targeting of ganglion cell axons to specific compartments (e.g. whisker follicles) of the mystacial pad and to specific regions of the brainstem. Experiments are outlined to use available antibody probes and anatomical tracers to analyze the development of the whisker pad, and of the parallel morphogenesis of axons that innervate it. First the stages of trigeminal axon growth, and the sequential development of whisker pad will be determined. The expression of NTs and their receptors (NTRs) (trkA, trkB, trkC, p75NGFR) will be mapped during the time of their peak expression in the trigeminal system, and as they are down regulated to basal levels. Spatial and temporal correlations will be made between the localization of NTs in specific cutaneous fields, and the expression of the corresponding NTRs on afferents to that field. Similar correlations will be made in the trigeminal brainstem. Based on pilot data which show that NTs may also affect the growth mode (elongation vs. arborization) of trigeminal ganglion cell axons, we propose to directly test the effects of each of the NTs on the morphology of sensory neurons growing in culture. A corresponding in vivo paradigm will be used to administer NTs to the embryo before, during and after the period of normally-occurring cell death in order to test our understanding of the role of these important molecules in the living animals as it matures.
