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miRNAs, ‘stemness’ and skin

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The epidermis and its appendages provide organisms with protection from the environment, keeping pathogens out and preventing the loss of essential body fluids. To perform both functions, the skin has elaborated a complex differentiation process known as cornification. The renewal capacity of the skin, which is responsible for maintaining tissue homeostasis, regenerating hair and repairing the epidermis after injury, resides in the basal proliferating compartment in which epidermal stem cells are located. These cells possess the remarkable capacity to both self-perpetuate and give rise to the differentiating cells that form mature tissues. Recent findings indicate that microRNAs have an essential role in orchestrating the formation of epidermis and skin appendages, in particular, at the interface between stemness and differentiation.

Section snippets

Are miRNAs expressed in skin?

MicroRNAs (miRNAs; see Glossary) are a class of non-coding RNA genes, the products of which are small single-stranded RNAs of 19–22 nucleotides (nts) that can suppress the expression of protein-coding genes by targeting the 3′UTR region of messenger RNAs (mRNAs) 1, 2, 3, 4 (Box 1). Studies in animal models have revealed essential functions for miRNAs in developmental control. Indeed, many miRNAs exhibit a temporal or tissue-specific expression pattern, indicating that they might have a crucial

miRNAs are important for skin development and homeostasis

To determine whether miRNAs are globally important for epidermal and hair follicle development, Dicer was specifically deleted in the epidermis 32, 33. Dicer is expressed in epidermis and in developing hair follicles both in mouse embryos (at the embryonic [E] 14.5 stage in which primary hair follicle development is initiated) and postnatally, as shown by in situ hybridization [33]. Conditional ablation in embryonic skin progenitors was achieved using Cre recombinase driven by the K14 promoter,

miRNA expression in the epidermis and hair follicle

Using two different microarray approaches, the Fuchs and Millar laboratories identified specific miRNAs expressed in developing mouse skin and hair follicles 32, 33. The Fuchs laboratory isolated and cloned small RNAs from E17.5 epidermis and hair follicles [32] (Table 1). By contrast, the Millar laboratory [33] identified miRNAs in full-thickness skin samples at postnatal day 1 and compared them with the miRNAs expressed in full-thickness skin of K14::DKK 1 (Dickkopf 1) transgenic mice (DKK1

miRNA-203 regulates the exit from ‘stemness’

miRNA-203 is abundantly expressed in the epidermis and in hair follicles between the E13.5 and E15.5 developmental stages. Its expression is absent in single-layered epidermal progenitors during early developmental stages but appears at E14.5 upon the induction of stratification [30]. In adult epidermis, miRNA-203 is not expressed in proliferating basal-layer keratinocytes but is detectable in the upper layers. Moreover, miRNA-203 is rapidly upregulated when primary keratinocytes isolated from

miRNAs are deregulated in epidermal diseases and tumours

miRNA expression profiles differ between healthy human skin and two chronic inflammatory diseases: psoriasis and atopic eczema [39] (Table 2). The differences include miRNA-21 upregulation in both diseases and specific miRNA-203 upregulation in psoriasis. miRNA-122 is downregulated in both psoriasis and atopic eczema, whereas miRNA-99b downregulation is observed specifically in psoriasis. The significant miRNA-203 upregulation in psoriatic plaques coincides with the downregulation of a

Concluding remarks and future perspectives

These new findings add epidermal development to the extensive role of miRNAs in overall animal development (as shown by the global Dicer disruption) and demonstrate that specific miRNAs participate in lineage differentiation in a wide variety of tissue types. The further investigation and elucidation of the molecular pathways that induce miRNA expression in skin will increase our understanding of the molecular mechanisms underlying skin diseases. Although studies of miRNAs in the epidermis

Acknowledgements

We thank Anna Maria Lena, Pia Rivetti di Val Cervo and Alessandro Terrinoni for scientific discussion. Work in our laboratory was supported by the Medical Research Council (to G.M.) and by grants from Telethon (GGP02251 to E.C.), AIRC (2743 to G.M.), EU (LSGBH-2005–019067-Epistem; LSHC-CT-2004–503576-Active p53) to G.M., MIUR to G.M., PRIN 06 to E.C., PRIN 06 to G.M., MinSan to G.M., ISS ‘Programma Italia–USA’ N526D5 to G.M., Philip Morris USA Inc. to G.M., ACC12 to G.M. and E.C. and by ANR

Glossary

Adult (or somatic) stem cells
undifferentiated cells found within a differentiated tissue that can renew themselves and differentiate (with certain limitations) to give rise to all the specialized cell types of the tissue from which it originated.
Dicer
a member of the RNase III family of nucleases that specifically cleaves double-stranded RNAs. Dicer processes long dsRNA into siRNAs of 21–23 nt.
Differentiation
the general process whereby an undifferentiated embryonic cell acquires the features of a

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