Investigation of regulatory functions of micrornas in skin and hair follicle development and cycling. A role of microRNA-214 in skin and hair follicle homeostasis.

Abstract

miRNAs are important post-transcriptional regulators of gene expression which play vital roles in the arrays of physiological processes, including skin and hair follicle (HF) development. In this study, the role for miR-214 in the skin and HF development and their postnatal physiological regeneration was investigated. miR-214 exhibits discrete expression patterns in the epidermis and HF in developing and postnatal skin, and is highly expressed in the epithelial stem cells and their lineage-committed progenies. The effects of miR-214 on HF morphogenesis and cycle progression were evaluated by using doxycyclineinducible miR-214 transgenic mice (K14-rtTA/TRE-miR-214). Keratinocyte specific miR-214 overexpression during skin embryogenesis resulted in the partial inhibition of HF induction and formation of the HF reduced in size producing thinner hair. Overexpression of miR-214 in telogen skin caused retardation of the anagen progression and HF growth. Inhibitory effects of miR- 214 on HF development and cycling were associated with supressed activity of stem cells, reduced proliferation in the hair matrix, and altered differentiation. miR-214 induced complex changes in gene expression programs in keratinocytes, including inhibition of cyclins and cyclin-dependent kinases and several essential components of Wnt, Edar, Shh and Bmp signalling pathways, whereas ����-catenin acts as a novel conserved miR-214 target. Indeed, the inhibitory effects of miR-214 on HF development were rescued by intracutaneous delivery of pharmacological Wnt activator. Thus, this study demonstrated that by targeting ����-catenin and, therefore, interfering with Wnt signalling activity miR-214 may act as one of the upstream effectors of the signalling cascades which govern HF morphogenesis and cycling.