Botchkarev Vladimir A, Botchkareva Natalia V, Peters Eva M, Paus Ralf
Department of Dermatology, Boston University School of Medicine, Boston, MA, USA.
Prog Brain Res. 2004;146:493-513. doi: 10.1016/S0079-6123(03)46031-7.
Neurotrophins (NTs) exert many growth-regulatory functions beyond the nervous system. For example, murine hair follicles (HF) show developmentally and spatio-temporally stringently controlled expression of NTs, including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and NT-4, and their cognate receptors, tyrosine kinase A-C (TrkA-C) and p75 neurotrophin receptor (p75NTR). Follicular NT and NT receptor expression exhibit significant, hair cycle-dependent fluctuations on the gene and protein level, which are mirrored by changes in nerve fiber density and neurotransmitter/neuropeptide content in the perifollicular neural networks. NT-3/TrkC and NGF/TrkA signaling stimulate HF development, while NT-3, NT-4 and BDNF inhibit the growth (anagen) of mature HF by the induction of apoptosis-driven HF regression (catagen). p75NTR stimulation inhibits HF development and stimulates catagen. Since the HF is thus both a prominent target and key peripheral source of NT, dissecting the role of NTs in the control of HF morphogenesis and cyclic remodeling provides a uniquely accessible, and easily manipulated, clinically relevant experimental model, which has many lessons to teach. Given that our most recent data also implicate NTs in human hair growth control, selective NT receptor agonists and antagonists may become innovative therapeutic tools for the management of hair growth disorders (alopecia, effluvium, hirsutism). Since, however, the same NT receptor agonists that inhibit hair growth (e.g., BDNF, NT-4) can actually stimulate epidermal keratinocyte proliferation, NT may exert differential effects on defined keratinocyte subpopulations. The studies reviewed here provide new clues to understanding the complex roles of NT in epithelial tissue biology and remodeling in vivo, and invite new applications for synthetic NT receptor ligands for the treatment of epithelial growth disorders, exploiting the HF as a lead model.
神经营养因子（NTs）在神经系统之外发挥着许多生长调节功能。例如，小鼠毛囊（HF）显示出NTs在发育过程中和时空上受到严格控制的表达，包括神经生长因子（NGF）、脑源性神经营养因子（BDNF）、神经营养因子-3（NT-3）和NT-4，以及它们的同源受体，酪氨酸激酶A-C（TrkA-C）和p75神经营养因子受体（p75NTR）。毛囊NTs和NTs受体的表达在基因和蛋白质水平上表现出显著的、依赖毛发生长周期的波动，这反映在毛囊周围神经网络中神经纤维密度和神经递质/神经肽含量的变化上。NT-3/TrkC和NGF/TrkA信号传导刺激毛囊发育，而NT-3、NT-4和BDNF通过诱导凋亡驱动的毛囊退化（退行期）来抑制成熟毛囊的生长（生长期）。p75NTR刺激抑制毛囊发育并刺激退行期。由于毛囊既是NTs的重要靶点又是关键的外周来源，剖析NTs在控制毛囊形态发生和周期性重塑中的作用提供了一个独特的、易于获取且易于操作的临床相关实验模型，从中可以学到很多东西。鉴于我们最近的数据也表明NTs参与人类毛发生长控制，选择性NTs受体激动剂和拮抗剂可能成为治疗毛发生长障碍（脱发、斑秃、多毛症）的创新治疗工具。然而，由于抑制毛发生长的相同NTs受体激动剂（例如BDNF、NT-4）实际上可以刺激表皮角质形成细胞增殖，NTs可能对特定的角质形成细胞亚群产生不同的影响。本文综述的研究为理解NTs在体内上皮组织生物学和重塑中的复杂作用提供了新线索，并为利用毛囊作为主要模型开发用于治疗上皮生长障碍的合成NTs受体配体带来了新的应用前景。
