DIFFERENTIAL DEPENDENCY OF UNMYELINATED AND A-DELTA EPIDERMAL AND UPPER DERMAL INNERVATION ON NEUROTROPHINS, TRK RECEPTORS, AND P75(LNGFR)

The impact of the nerve growth factor (NGF) family of neurotrophins an d their receptors was examined on the cutaneous innervation in the mys tacial pads of mice. Ten sets of unmyelinated and thinly myelinated se nsory and autonomic innervation were evaluated that terminated in the epidermis, upper dermis, and upper part of the intervibrissal hair fol licles. Mystacial pads were analyzed from newborn to 4-week-old mice t hat had homozygous functional deletions of the genes for NGF, brain-de rived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin- il (NT-4), tyrosine kinase (trk) A, trkB, trkC, or p75. Mystacial pads were also analyzed in adult transgenic mice that had overproduction o f NGF, BDNF, or NT-3 driven by a keratin promoter gene. The innervatio n was revealed by using immunofluorescence and immunocytochemistry wit h antibodies for protein gene product (PGP) 9.5, calcitonin gene-relat ed product (CGRP), substance P (SP), galanin (GAL), neuropeptide Y (NP Y), tyrosine hydroxylase (TH), and a neurofilament protein. The cumula tive results indicated that NGF/trkA signaling plays a major role in t he outgrowth and proliferation of sensory axons, whereas NT-3/ trkA si gnaling plays a major role in the formation of sensory endings. TrkC i s also essential for the development of three sets of trkA-dependent s ensory innervation that coexpress CGRP, SP, and GAL. Another set of se nsory innervation that only coexpressed CGRP and SP was solely depende nt upon NGF and trkA. Surprisingly, most sets of trkA-dependent sensor y innervation are suppressed by trkB perhaps interacting with p75. BDN F and NT-4 appear to mediate this suppressing effect in the upper derm is and NT-4 in the epidermis. In contrast to sensory innervation, symp athetic innervation to the necks of intervibrissal hair follicles depe nds upon NGF/trkA signaling interacting with p75 for both the axon out growth and ending formation. Although NT-3/trkA signaling is essential for the full complement of sympathetic neurons, NT-3 is detrimental t o the formation of sympathetic terminations to the necks of hair folli cles. TrkB signaling mediated by BDNF but not NT-4 also suppresses the se sympathetic terminations. One sparse set of innervation, perhaps pa rasympathetic, terminating at the necks of hair follicles is dependent solely upon NT-3 and trkC. Taken together, our results indicate that the innervation of the epidermis, upper dermis, and the upper portion of hair follicles is regulated by a competitive balance between promot ing and suppressing effects of the various neurotrophins. (C) 1998 Aca demic Press.