skin cells - Vol 452 | 13 March 2008 |...

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LETTERS A skin microRNA promotes differentiation by repressing ‘stemness’ Rui Yi 1,2 , Matthew N. Poy 3 , Markus Stoffel 3 1,2 In stratified epithelial tissues, homeostasis relies on the self- renewing capacity of stem cells located within the innermost basal layer 1 . As basal cells become suprabasal, they lose proliferative potential and embark on a terminal differentiation programme 2,3 . Here, we show that microRNA-203 is induced in the skin concom- itantlywithstratificationanddifferentiation.ByalteringmiR-203’s spatiotemporal expression in vivo , we show that miR-203 pro- motes epidermal differentiation by restricting proliferative poten- tial and inducing cell-cycle exit. We identify p63 as one of the conserved targets of miR-203 across vertebrates. Notably, p63 is an essential regulator of stem-cell maintenance in stratified epi- thelial tissues 4–9 . We show that miR-203 directly represses the expression of p63 : it fails to switch off suprabasally when either Dicer1 or miR-203 is absent and it becomes repressed basally when miR-203 is prematurely expressed. Our findings suggest that miR-203 defines a molecular boundary between proliferative basal progenitors and terminally differentiating suprabasal cells, ensuring proper identity of neighbouring layers. MicroRNAs are small, non-coding RNAs that regulate gene expression post-transcriptionally by directly targeting RNA-induced silencing complex (RISC) to cognate messenger RNA targets 10 . When miRNAs are globally ablated in skin epithelium by conditionally targeting the gene that encodes the miRNA-processing enzyme Dicer1, hair follicles fail to invaginate. This distorts epidermal mor- phology, compromising the barrier and underscoring the functional importance of these small RNAs in skin development 11,12 . To gain further insight into the possible significance of different skin miRNAs, we constructed epidermal miRNA libraries using total RNAs isolated from pure epidermis starting from embryonic day 13.5 (E13.5), when it is still a single-layered epithelium, to postnatal day 4.5 (P4.5), when it is fully stratified. Among more than 100 epidermal miRNAs cloned, miR-203 barely surfaced in the pool of E13.5 clones but emerged as one of the most abundant epidermal miRNAs from E15.5 onwards (Fig. 1a). The significant upregulation of miR-203 between E13.5 and E15.5 was suggestive that this miRNA may be absent in multipotent pro- genitors of single-layered epidermis, but is induced upon stratifica- tion and differentiation. By in situ hybridization 13 , miR-203 was largely confined to suprabasal cells of epithelial tissues, and was espe- cially prominent in skin (Fig. 1b, d, e and Supplementary Fig. 1). The specificity of hybridization was confirmed by analysing conditionally ablated Dicer1 skin, in which expression of miR-203 and other mature miRNAs was abolished 11 (Supplementary Fig. 1a). Quantifi- cation of its differential expression by quantitative PCR with reverse transcription (qRT–PCR) revealed
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This note was uploaded on 04/26/2010 for the course SCI 35254 taught by Professor George during the Spring '10 term at Aarhus Universitet.

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skin cells - Vol 452 | 13 March 2008 |...

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