Rice F L, Albers K M, Davis B M, Silos-Santiago I, Wilkinson G A, LeMaster A M, Ernfors P, Smeyne R J, Aldskogius H, Phillips H S, Barbacid M, DeChiara T M, Yancopoulos G D, Dunne C E, Fundin B T
Department of Pharmacology and Neuroscience, Albany Medical College, New York 12208, USA.
Dev Biol. 1998 Jun 1;198(1):57-81.
The impact of the nerve growth factor (NGF) family of neurotrophins and their receptors was examined on the cutaneous innervation in the mystacial pads of mice. Ten sets of unmyelinated and thinly myelinated sensory and autonomic innervation were evaluated that terminated in the epidermis, upper dermis, and upper part of the intervibrissal hair follicles. Mystacial pads were analyzed from newborn to 4-week-old mice that had homozygous functional deletions of the genes for NGF, brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4), tyrosine kinase (trk) A, trkB, trkC, or p75. Mystacial pads were also analyzed in adult transgenic mice that had overproduction of NGF, BDNF, or NT-3 driven by a keratin promoter gene. The innervation was revealed by using immunofluorescence and immunocytochemistry with antibodies for protein gene product (PGP) 9.5, calcitonin gene-related product (CGRP), substance P (SP), galanin (GAL), neuropeptide Y (NPY), tyrosine hydroxylase (TH), and a neurofilament protein. The cumulative results indicated that NGF/trkA signaling plays a major role in the outgrowth and proliferation of sensory axons, whereas NT-3/ trkA signaling plays a major role in the formation of sensory endings. TrkC is also essential for the development of three sets of trkA-dependent sensory innervation that coexpress CGRP, SP, and GAL. Another set of sensory innervation that only coexpressed CGRP and SP was solely dependent upon NGF and trkA. Surprisingly, most sets of trkA-dependent sensory innervation are suppressed by trkB perhaps interacting with p75. BDNF and NT-4 appear to mediate this suppressing effect in the upper dermis and NT-4 in the epidermis. In contrast to sensory innervation, sympathetic innervation to the necks of intervibrissal hair follicles depends upon NGF/trkA signaling interacting with p75 for both the axon outgrowth and ending formation. Although NT-3/trkA signaling is essential for the full complement of sympathetic neurons, NT-3 is detrimental to the formation of sympathetic terminations to the necks of hair follicles. TrkB signaling mediated by BDNF but not NT-4 also suppresses these sympathetic terminations. One sparse set of innervation, perhaps parasympathetic, 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 promoting and suppressing effects of the various neurotrophins.
研究了神经营养因子的神经生长因子（NGF）家族及其受体对小鼠触须垫皮肤神经支配的影响。评估了十组终止于表皮、真皮上层和触须间毛囊上部的无髓鞘和薄髓鞘感觉及自主神经支配。对新生至4周龄的小鼠触须垫进行了分析，这些小鼠的NGF、脑源性神经营养因子（BDNF）、神经营养因子-3（NT-3）、神经营养因子-4（NT-4）、酪氨酸激酶（trk）A、trkB、trkC或p75基因存在纯合功能性缺失。还对由角蛋白启动子基因驱动NGF、BDNF或NT-3过度产生的成年转基因小鼠的触须垫进行了分析。通过使用针对蛋白基因产物（PGP）9.5、降钙素基因相关产物（CGRP）、P物质（SP）、甘丙肽（GAL）、神经肽Y（NPY）、酪氨酸羟化酶（TH）和神经丝蛋白的抗体进行免疫荧光和免疫细胞化学来显示神经支配。累积结果表明，NGF/trkA信号传导在感觉轴突的生长和增殖中起主要作用，而NT-3/trkA信号传导在感觉末梢的形成中起主要作用。TrkC对于三组共表达CGRP、SP和GAL的trkA依赖性感觉神经支配的发育也是必不可少的。另一组仅共表达CGRP和SP的感觉神经支配完全依赖于NGF和trkA。令人惊讶的是，大多数trkA依赖性感觉神经支配可能受trkB与p75相互作用的抑制。BDNF和NT-4似乎在上层真皮中介导这种抑制作用，而NT-4在表皮中介导这种作用。与感觉神经支配相反，触须间毛囊颈部的交感神经支配在轴突生长和末梢形成方面都依赖于NGF/trkA信号传导与p75的相互作用。虽然NT-3/trkA信号传导对于交感神经元的完整补充是必不可少的，但NT-3对毛囊颈部交感末梢的形成是有害的。由BDNF而非NT-4介导的TrkB信号传导也抑制这些交感末梢。一组稀疏的、可能是副交感神经的神经支配终止于毛囊颈部，仅依赖于NT-3和trkC。综上所述，我们的结果表明，表皮、真皮上层和毛囊上部的神经支配受各种神经营养因子促进和抑制作用之间竞争平衡的调节。
