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Not miR‐ly micromanagers: the functions and regulatory networks of microRNAs in mammalian skin

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The microRNA (miRNA) pathway is a widespread mechanism of post‐transcriptional gene regulation in eukaryotic cells. In animals, each miRNA species can regulate hundreds of protein‐coding genes, resulting in pervasive functions for miRNAs in numerous cellular processes. Since the identification of the first mammalian miRNA, the function of miRNAs in mammals has been a topic of great interest, both because of the versatile roles of miRNAs in biological systems, as well as the clinical potential of these regulatory RNAs. With well‐defined cell lineages and the availability of versatile tools for both in vivo and in vitro studies, mammalian skin has emerged as an important system in which to examine miRNAs' functions in adult tissues. In this review, we discuss recent insights into the functions and regulatory networks of miRNAs in mammals, with a specific focus on murine skin development as a model system. We first introduce functional analyses of the miRNA biogenesis pathway in the skin, then highlight the functions of individual miRNAs in skin development, followed by an examination of miRNA roles in skin stress responses. We finish with a discussion of miRNA regulatory networks and emphasize future challenges and emerging technologies that permit the genome‐wide study of miRNA functions and regulatory mechanisms in mammalian skin. WIREs RNA 2014, 5:849–865. doi: 10.1002/wrna.1250 This article is categorized under: Regulatory RNAs/RNAi/Riboswitches > RNAi: Mechanisms of Action Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs RNA in Disease and Development > RNA in Disease RNA in Disease and Development > RNA in Development
Conceptual functions for microRNA (miRNA) targeting in networks. (a) miRNAs can act to reinforce a cellular state by promoting negative regulation of factors. In this case, miR‐203 antagonizes ΔNp63 during the epidermal differentiation. We note that miR‐203 represses many other genes in addition to ΔNp63 during the transition. (b) By imparting negative regulation to transcripts, miRNAs can buffer biological noise inherent in gene expression networks. By suppressing noise in gene expression, miRNAs contribute to establishing thresholds at which target genes must cross to promote a relevant cellular outcome. (c) One of the barriers in studying miRNA function in complex biological systems is that many mRNAs are under coordinated regulation by multiple miRNAs. Shown are representative Ago2 HITS‐CLIP tags mapping to ΔNp63's 3′UTR. miR‐130b and miR‐203 have both independently been demonstrated to regulate ΔNp63, and shown here both co‐target ΔNp63 in keratinocytes. (d) Further complexity in dissecting miRNAs function on a genome‐wide scale is introduced by competing endogenous RNAs (ceRNAs). ceRNAs, such as pseudogenes or circular RNAs, titrate away active RISC from mRNA targets, thereby influencing miRNA repressive activities.
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MicroRNAs (miRNAs) regulate a variety of processes involved in stress responses. The skin undergoes a variety of stresses, including wound healing, viral infection, and tumorigenesis. Examples of specific miRNA regulation have been uncovered for most of the major processes which contribute to these stress responses. However, our understanding of how miRNAs are involved in regulating stress responses is incomplete, and extensive effort will be required to extend our comprehension.
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Murine skin is comprised of a variety of cell lineages within the interfollicular epidermis and hair follicle. In the interfollicular epidermis, proliferative basal cells contribute to the above layers of differentiating cells, which perform the barrier function of the skin. Within those differentiated cells, miR‐203 and miR‐24 regulate proliferation and actin‐cytoskeletal dynamics, respectively. The hair follicle is comprised of cells at varying stages of differentiation. A subset of hair follicle stem cells (HFSCs) housed in the bulge differentiate and move downwards to become the highly proliferative, transit‐amplifying cells of the matrix. Those cells then differentiate to become the inner and outer root sheaths. The balance of quiescence and differentiation in HFSCs is maintained in part by miR‐205 and miR‐125b. Within the inner root sheath, miR‐24 ensures that self‐renewal is repressed and differentiation is preferred. Finally, within the sebaceous gland, an accessory structure to the hair follicle, miR‐125b contributes to the control of proliferation. In addition to the examples shown, there are likely to be additional microRNAs (miRNAs) with important functions in the various cell types of the interfollicular epidermis and hair follicle that have yet to be uncovered.
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Regulatory RNAs/RNAi/Riboswitches > RNAi: Mechanisms of Action
RNA in Disease and Development > RNA in Development
Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs
RNA in Disease and Development > RNA in Disease

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