Foxi3 Deficiency Compromises Hair Follicle Stem Cell Specification and Activation.
Foxi3 Deficiency Compromises Hair Follicle Stem Cell Specification and Activation.
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DOI：
10.1002/stem.2363
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发表时间：
2016-07
期刊：
影响因子：
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通讯作者：
Mikkola ML
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文献类型：
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作者：
Shirokova V;Biggs LC;Jussila M;Ohyama T;Groves AK;Mikkola ML
毛囊是研究干细胞规格和动态平衡的理想系统，因为它具有良好的形态发生和干细胞激活的典型周期，每个毛发周期都会产生新的毛干。成人毛囊干细胞生态位由两个不同的群体组成，凸起和更容易激活的次级毛胚。毛囊干细胞在形态发生的早期阶段被搁置。已知这一过程依赖于Sox9转录因子，但除此之外，人们对毛囊干细胞生态位的建立知之甚少。在这里，我们展示了FoxI3突变，一种在几个无毛狗品种中突变的叉头家族转录因子，损害了干细胞的规格。此外，foxI3的丢失会阻碍毛囊的生长和毛发周期的进展。全基因组图谱显示了foxI3的一些下游效应因子，包括在毛囊干细胞中具有公认功能的转录因子，如LHX2、RUNX1和NFATc1，表明foxI3突变表型是几个干细胞特征基因同时下调的结果。我们发现foxI3在毛发形态发生和毛发周期过程中表现出高度动态的表达模式，并确定foxI3是一个新的次级毛发生殖细胞标记。缺少foxI3会导致拔毛后毛发再生不良，在无动于衷的小鼠中会出现稀疏的毛皮表型，这种表型会随着年龄的增长而恶化，这是由于次级毛囊激活受损导致干细胞逐渐枯竭造成的。因此，foxI3调节毛囊发育和动态平衡的多个方面。
The hair follicle is an ideal system to study stem cell specification and homeostasis due to its well characterized morphogenesis and stereotypic cycles of stem cell activation upon each hair cycle to produce a new hair shaft. The adult hair follicle stem cell niche consists of two distinct populations, the bulge and the more activation-prone secondary hair germ. Hair follicle stem cells are set aside during early stages of morphogenesis. This process is known to depend on the Sox9 transcription factor, but otherwise the establishment of the hair follicle stem cell niche is poorly understood. Here we show that that mutation of Foxi3, a Forkhead family transcription factor mutated in several hairless dog breeds, compromises stem cell specification. Further, loss of Foxi3 impedes hair follicle downgrowth and progression of the hair cycle. Genome-wide profiling revealed a number of downstream effectors of Foxi3 including transcription factors with a recognized function in hair follicle stem cells such as Lhx2, Runx1, and Nfatc1, suggesting that the Foxi3 mutant phenotype results from simultaneous downregulation of several stem cell signature genes. We show that Foxi3 displays a highly dynamic expression pattern during hair morphogenesis and cycling, and identify Foxi3 as a novel secondary hair germ marker. Absence of Foxi3 results in poor hair regeneration upon hair plucking, and a sparse fur phenotype in unperturbed mice that exacerbates with age, caused by impaired secondary hair germ activation leading to progressive depletion of stem cells. Thus, Foxi3 regulates multiple aspects of hair follicle development and homeostasis.