Inducible deletion of epidermal Dicer and Drosha reveals multiple functions for miRNAs in postnatal skin

Abstract

SUMMARYMicroRNAs (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.

A multifunctional protein EWS regulates the expression of Drosha and microRNAs

“…In this context, EWS modulation of Drosha and miRNAs may enhance the expression of Col4a1 and CTGF to improve dermal morphogenesis. 18 In summary, we provide evidence that EWS modulates the expression of Col4a1 and CTGF by regulating miRNA29b and miRNA-18b (Figure 6g). Furthermore, increased Drosha expression mediates the processing of pre-miRNAs, promoting the biogenesis of miR-29b and miR-18b, and subsequently reducing post-transcription levels of Col4a1 and CTGF under EWS deficiency.…”

“…Recent studies report that miRNAs have a quite important role in skin development. 18 EWS has been found in the complex containing Drosha by mass spectrometry analysis. 19 However, the role of EWS in miRNA biogenesis or regulation has not been studied.…”

Regulation of microRNA function in somatic stem cell proliferation and differentiation

“…miRNA loss in the developing epidermis also promotes hyper-proliferation and apoptosis 62,63 . In postnatal skin, the loss of Dicer in the hair follicle leads to defects during the growth phase (anagen) and entry into the regression phase (catagen) but resting hair follicles are relatively unaffected 64 ; by contrast, the interfollicular epidermis exhibits increased proliferation. These data suggest diverse roles of miRNAs in regulating the various skin lineages, consistent with findings associated with functional dissection of individual miRNAs (FIG.…”

Dicer Cooperates with p53 to Suppress DNA Damage and Skin Carcinogenesis in Mice

“…Once born, these pups failed to gain weight, and most died within a week of birth presumably due to issues related to dehydration and failure to thrive. In keeping with these reports, a recent study employing mice bearing conditional Dicer or Drosha alleles and a temporally-inducible Keratin15-promoter determined that induced postnatal ablation of either miRNA processing enzyme reduced the survival of rapidly proliferating matrix population of cells that normally form the hair shaft during the anagen phase of the hair cycle [21]. Apoptosis within the matrix population led to a dermal inflammatory response, hyper-proliferation of the interfollicular epidermis, and degradation of the hair follicle.…”