Department of Dermatology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
Development. 2012 Apr;139(8):1405-16. doi: 10.1242/dev.070920.
MicroRNAs (miRNAs) regulate the expression of many mammalian genes and play key roles in embryonic hair follicle development; however, little is known of their functions in postnatal hair growth. We compared the effects of deleting the essential miRNA biogenesis enzymes Drosha and Dicer in mouse skin epithelial cells at successive postnatal time points. Deletion of either Drosha or Dicer during an established growth phase (anagen) caused failure of hair follicles to enter a normal catagen regression phase, eventual follicular degradation and stem cell loss. Deletion of Drosha or Dicer in resting phase follicles did not affect follicular structure or epithelial stem cell maintenance, and stimulation of anagen by hair plucking caused follicular proliferation and formation of a primitive transient amplifying matrix population. However, mutant matrix cells exhibited apoptosis and DNA damage and hair follicles rapidly degraded. Hair follicle defects at early time points post-deletion occurred in the absence of inflammation, but a dermal inflammatory response and hyperproliferation of interfollicular epidermis accompanied subsequent hair follicle degradation. These data reveal multiple functions for Drosha and Dicer in suppressing DNA damage in rapidly proliferating follicular matrix cells, facilitating catagen and maintaining follicular structures and their associated stem cells. Although Drosha and Dicer each possess independent non-miRNA-related functions, the similarity in phenotypes of the inducible epidermal Drosha and Dicer mutants indicates that these defects result primarily from failure of miRNA processing. Consistent with this, Dicer deletion resulted in the upregulation of multiple direct targets of the highly expressed epithelial miRNA miR-205.
微小 RNA（miRNAs）调节许多哺乳动物基因的表达，在胚胎毛囊发育中发挥关键作用；然而，它们在出生后毛发生长中的作用知之甚少。我们比较了在连续的出生后时间点在小鼠皮肤上皮细胞中删除必需的 miRNA 生物发生酶 Drosha 和 Dicer 的影响。在已建立的生长阶段（生长期）中删除 Drosha 或 Dicer 会导致毛囊无法进入正常的退行阶段（退行期），最终导致毛囊退化和干细胞丢失。在静止期毛囊中删除 Drosha 或 Dicer 不会影响毛囊结构或上皮干细胞的维持，并且通过拔毛刺激生长期会导致毛囊增殖和形成原始的短暂扩增基质细胞群。然而，突变的基质细胞表现出细胞凋亡和 DNA 损伤，并且毛囊迅速退化。早期删除后发生的毛囊缺陷在没有炎症的情况下发生，但随后的毛囊退化伴随着真皮炎症反应和滤泡间表皮的过度增殖。这些数据揭示了 Drosha 和 Dicer 在抑制快速增殖的毛囊基质细胞中的 DNA 损伤、促进退行期和维持毛囊结构及其相关干细胞方面的多种功能。尽管 Drosha 和 Dicer 各自具有独立的非 miRNA 相关功能，但可诱导的表皮 Drosha 和 Dicer 突变体的表型相似表明这些缺陷主要是由于 miRNA 加工失败。与此一致，Dicer 的缺失导致高度表达的上皮 miRNA miR-205 的多个直接靶标上调。
