Role of epidermal primary cilia in the homeostasis of skin and hair follicles
Role of epidermal primary cilia in the homeostasis of skin and hair follicles
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DOI：
10.1242/dev.060210
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发表时间：
2011-05-01
期刊：
影响因子：
4.6
通讯作者：
Yoder, Bradley K.
中科院分区：
文献类型：
--
作者：
Croyle, Mandy J.;Lehman, Jonathan M.;Yoder, Bradley K.
皮肤和毛囊的形态发生和动态平衡需要多种信号通路的整合，包括Hedgehog(HH)和Wingless(Wnt)，以及定向细胞分裂，所有这些都与初级纤毛有关。尽管研究表明，破坏真皮纤毛会导致卵泡停止并减弱HH信号，但对表皮纤毛的作用知之甚少。在这里，利用纤毛发生基因Ift88和Kif3a的条件等位基因来分析表皮纤毛的功能。出生时，表皮纤毛突变体看起来正常，但随着年龄的增长，出现基底样增生并长入腹侧真皮。尾部毛囊排列紊乱，皮脂腺小叶增多。表皮纤毛突变体显示较少的长期标记保留细胞，这表明干细胞动态平衡发生了变化。从谱系追踪研究中可以明显看到异常的增殖和分化，并显示滤泡细胞扩张到毛囊间表皮，就像在伤口修复过程中所见。这些表型与典型的Wnt活性或定向细胞分裂的变化无关。然而，参与层化、角质形成细胞分化和伤口修复的Delta Np63转录因子的核积累增加，而HH途径受到抑制。有趣的是，这些表型并不是典型的与HH信号丢失相关的表型，但与Delta Np63在表皮过度表达的小鼠的表型相似。总之，这些数据表明，表皮初级纤毛可能在应激反应和表皮内稳态中发挥作用，涉及的途径不同于通常与初级纤毛相关的途径。
Skin and hair follicle morphogenesis and homeostasis require the integration of multiple signaling pathways, including Hedgehog (Hh) and Wingless (Wnt), and oriented cell divisions, all of which have been associated with primary cilia. Although studies have shown that disrupting dermal cilia causes follicular arrest and attenuated Hh signaling, little is known about the role of epidermal cilia. Here, epidermal cilia function was analyzed using conditional alleles of the ciliogenic genes Ift88 and Kif3a. At birth, epidermal cilia mutants appeared normal, but developed basaloid hyperplasia and ingrowths into the dermis of the ventrum with age. In addition, follicles in the tail were disorganized and had excess sebaceous gland lobules. Epidermal cilia mutants displayed fewer long-term label-retaining cells, suggesting altered stem cell homeostasis. Abnormal proliferation and differentiation were evident from lineage-tracing studies and showed an expansion of follicular cells into the interfollicular epidermis, as is seen during wound repair. These phenotypes were not associated with changes in canonical Wnt activity or oriented cell division. However, nuclear accumulation of the Delta Np63 transcription factor, which is involved in stratification, keratinocyte differentiation and wound repair, was increased, whereas the Hh pathway was repressed. Intriguingly, the phenotypes were not typical of those associated with loss of Hh signaling but exhibited similarities with those of mice in which Delta Np63 is overexpressed in the epidermis. Collectively, these data indicate that epidermal primary cilia may function in stress responses and epidermal homeostasis involving pathways other than those typically associated with primary cilia.