Botchkarev V A, Botchkareva N V, Welker P, Metz M, Lewin G R, Subramaniam A, Bulfone-Paus S, Hagen E, Braun A, Lommatzsch M, Renz H, Paus A R
Department of Dermatology, Humboldt University, Berlin, D-13122 Germany.
FASEB J. 1999 Feb;13(2):395-410. doi: 10.1096/fasebj.13.2.395.
Neurotrophins exert many biological effects not directly targeted at neurons, including modulation of keratinocyte proliferation and apoptosis in vitro. Here we exploit the cyclic growth and regression activity of the murine hair follicle to explore potential nonneuronal functions of neurotrophins in the skin, and analyze the follicular expression and hair growth-modulatory function of BDNF, NT-4, and their high-affinity receptor, TrkB. The cutaneous expression of BDNF and NT-4 mRNA was strikingly hair cycle dependent and peaked during the spontaneous, apoptosis-driven hair follicle regression (catagen). During catagen, BDNF mRNA and immunoreactivity, as well as NT-4-immunoreactivity, were expressed in the regressing hair follicle compartments, whereas TrkB mRNA and immunoreactivity were seen in dermal papilla fibroblasts, epithelial strand, and hair germ. BDNF or NT-4 knockout mice showed significant catagen retardation, whereas BDNF-overexpressing mice displayed acceleration of catagen and significant shortening of hair length. Finally, BDNF and NT-4 accelerated catagen development in murine skin organ culture. Together, our data suggest that BDNF and NT-4 play a previously unrecognized role in skin physiology as agents of hair growth control. Thus, TrkB agonists and antagonists deserve exploration as novel hair growth-modulatory drugs for the management of common hair growth disorders.
神经营养因子发挥着许多并非直接作用于神经元的生物学效应，包括在体外调节角质形成细胞的增殖和凋亡。在此，我们利用小鼠毛囊的周期性生长和退行活动，来探究神经营养因子在皮肤中的潜在非神经元功能，并分析脑源性神经营因子（BDNF）、神经营养因子4（NT-4）及其高亲和力受体酪氨酸激酶受体B（TrkB）在毛囊中的表达及对毛发生长的调节功能。BDNF和NT-4 mRNA的皮肤表达显著依赖于毛发周期，并在自发的、由凋亡驱动的毛囊退行期（退行期）达到峰值。在退行期，BDNF mRNA和免疫反应性以及NT-4免疫反应性在退行的毛囊区域表达，而TrkB mRNA和免疫反应性则见于真皮乳头成纤维细胞、上皮索和毛芽中。BDNF或NT-4基因敲除小鼠表现出明显的退行期延迟，而BDNF过表达小鼠则显示退行期加速且毛发长度显著缩短。最后，BDNF和NT-4在小鼠皮肤器官培养中加速了退行期的发展。总之，我们的数据表明BDNF和NT-4在皮肤生理学中作为毛发生长控制因子发挥了以前未被认识的作用。因此，TrkB激动剂和拮抗剂作为用于治疗常见毛发生长障碍的新型毛发生长调节药物值得探索。
