Telerman Stephanie B, Rognoni Emanuel, Sequeira Inês, Pisco Angela Oliveira, Lichtenberger Beate M, Culley Oliver J, Viswanathan Priyalakshmi, Driskell Ryan R, Watt Fiona M
King's College London Centre for Stem Cells and Regenerative Medicine, Great Maze Pond, London, UK.
Medical University of Vienna, Skin and Endothelium Research Division (SERD), Department of Dermatology, Vienna, Austria.
J Invest Dermatol. 2017 Nov;137(11):2270-2281. doi: 10.1016/j.jid.2017.06.015. Epub 2017 Jun 28.
B-lymphocyte-induced maturation protein 1 (Blimp1) is a transcriptional repressor that regulates cell growth and differentiation in multiple tissues, including skin. Although in the epidermis Blimp1 is important for keratinocyte and sebocyte differentiation, its role in dermal fibroblasts is unclear. Here we show that Blimp1 is dynamically regulated in dermal papilla cells during hair follicle (HF) morphogenesis and the postnatal hair cycle, preceding dermal Wnt/β-catenin activation. Blimp1 ablation in E12.5 mouse dermal fibroblasts delayed HF morphogenesis and growth and prevented new HF formation after wounding. By combining targeted quantitative PCR screens with bioinformatic analysis and experimental validation we demonstrated that Blimp1 is both a target and a mediator of key dermal papilla inductive signaling pathways including transforming growth factor-β and Wnt/β-catenin. Epidermal overexpression of stabilized β-catenin was able to override the HF defects in Blimp1 mutant mice, underlining the close reciprocal relationship between the dermal papilla and adjacent HF epithelial cells. Overall, our study reveals the functional role of Blimp1 in promoting the dermal papilla inductive signaling cascade that initiates HF growth.
B淋巴细胞诱导成熟蛋白1(Blimp1)是一种转录抑制因子,可调节包括皮肤在内的多种组织中的细胞生长和分化。尽管在表皮中Blimp1对角质形成细胞和皮脂腺细胞的分化很重要,但其在真皮成纤维细胞中的作用尚不清楚。在这里,我们表明在毛囊(HF)形态发生和出生后毛发周期中,Blimp1在真皮乳头细胞中受到动态调节,先于真皮Wnt/β-连环蛋白的激活。在E12.5小鼠真皮成纤维细胞中敲除Blimp1会延迟HF的形态发生和生长,并阻止伤口愈合后新HF的形成。通过将靶向定量PCR筛选与生物信息学分析和实验验证相结合,我们证明Blimp1既是关键真皮乳头诱导信号通路(包括转化生长因子-β和Wnt/β-连环蛋白)的靶点,也是其介导因子。稳定的β-连环蛋白在表皮中的过表达能够克服Blimp1突变小鼠中的HF缺陷,强调了真皮乳头与相邻HF上皮细胞之间密切的相互关系。总体而言,我们的研究揭示了Blimp1在促进启动HF生长的真皮乳头诱导信号级联反应中的功能作用。