Abstract
During embryogenesis, multipotent progenitors within the single-layered surface epithelium differentiate to form the epidermis and its appendages. Here, we show that microRNAs (miRNAs) have an essential role in orchestrating these events. We cloned more than 100 miRNAs from skin and show that epidermis and hair follicles differentially express discrete miRNA families. To explore the functional significance of this finding, we conditionally targeted Dicer1 gene ablation in embryonic skin progenitors. Within the first week after loss of miRNA expression, cell fate specification and differentiation were not markedly impaired, and in the interfollicular epidermis, apoptosis was not markedly increased. Notably, however, developing hair germs evaginate rather than invaginate, thereby perturbing the epidermal organization. Here we characterize miRNAs in skin, the existence of which was hitherto unappreciated, and demonstrate their differential expression and importance in the morphogenesis of epithelial tissues within this vital organ.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Bartel, D.P. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297 (2004).
Kim, V.N. MicroRNA biogenesis: coordinated cropping and dicing. Nat. Rev. Mol. Cell Biol. 6, 376–385 (2005).
Chen, C.Z., Li, L., Lodish, H.F. & Bartel, D.P. MicroRNAs modulate hematopoietic lineage differentiation. Science 303, 83–86 (2004).
Poy, M.N. et al. A pancreatic islet-specific microRNA regulates insulin secretion. Nature 432, 226–230 (2004).
He, L. et al. A microRNA polycistron as a potential human oncogene. Nature 435, 828–833 (2005).
O'Donnell, K.A., Wentzel, E.A., Zeller, K.I., Dang, C.V. & Mendell, J.T. c-Myc-regulated microRNAs modulate E2F1 expression. Nature 435, 839–843 (2005).
Wienholds, E. & Plasterk, R.H. MicroRNA function in animal development. FEBS Lett. 579, 5911–5922 (2005).
Zhao, Y., Samal, E. & Srivastava, D. Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis. Nature 436, 214–220 (2005).
Rendl, M., Lewis, L. & Fuchs, E. Molecular dissection of mesenchymal-epithelial interactions in the hair follicle. PLoS Biol. 3, e331 (2005).
Chen, P.Y. et al. The developmental miRNA profiles of zebrafish as determined by small RNA cloning. Genes Dev. 19, 1288–1293 (2005).
Griffiths-Jones, S. The microRNA Registry. Nucleic Acids Res. 32, D109–D111 (2004).
Fukagawa, T. et al. Dicer is essential for formation of the heterochromatin structure in vertebrate cells. Nat. Cell Biol. 6, 784–791 (2004).
Lewis, B.P., Burge, C.B. & Bartel, D.P. Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120, 15–20 (2005).
Xie, X. et al. Systematic discovery of regulatory motifs in human promoters and 3′ UTRs by comparison of several mammals. Nature 434, 338–345 (2005).
Bernstein, E. et al. Dicer is essential for mouse development. Nat. Genet. 35, 215–217 (2003).
Harfe, B.D., McManus, M.T., Mansfield, J.H., Hornstein, E. & Tabin, C.J. The RNaseIII enzyme Dicer is required for morphogenesis but not patterning of the vertebrate limb. Proc. Natl. Acad. Sci. USA 102, 10898–10903 (2005).
Muljo, S.A. et al. Aberrant T cell differentiation in the absence of Dicer. J. Exp. Med. 202, 261–269 (2005).
Cobb, B.S. et al. T cell lineage choice and differentiation in the absence of the RNase III enzyme Dicer. J. Exp. Med. 201, 1367–1373 (2005).
Kanellopoulou, C. et al. Dicer-deficient mouse embryonic stem cells are defective in differentiation and centromeric silencing. Genes Dev. 19, 489–501 (2005).
Murchison, E.P., Partridge, J.F., Tam, O.H., Cheloufi, S. & Hannon, G.J. Characterization of Dicer-deficient murine embryonic stem cells. Proc. Natl. Acad. Sci. USA 102, 12135–12140 (2005).
Kaufman, C.K. et al. GATA-3: an unexpected regulator of cell lineage determination in skin. Genes Dev. 17, 2108–2122 (2003).
Blanpain, C., Lowry, W.E., Geoghegan, A., Polak, L. & Fuchs, E. Self-renewal, multipotency, and the existence of two cell populations within an epithelial stem cell niche. Cell 118, 635–648 (2004).
Tumbar, T. et al. Defining the epithelial stem cell niche in skin. Science 303, 359–363 (2004).
Vasioukhin, V., Degenstein, L., Wise, B. & Fuchs, E. The magical touch: genome targeting in epidermal stem cells induced by tamoxifen application to mouse skin. Proc. Natl. Acad. Sci. USA 96, 8551–8556 (1999).
Raghavan, S., Bauer, C., Mundschau, G., Li, Q. & Fuchs, E. Conditional ablation of beta1 integrin in skin. Severe defects in epidermal proliferation, basement membrane formation, and hair follicle invagination. J. Cell Biol. 150, 1149–1160 (2000).
Dowling, J., Yu, Q.C. & Fuchs, E. Beta4 integrin is required for hemidesmosome formation, cell adhesion and cell survival. J. Cell Biol. 134, 559–572 (1996).
van der Neut, R., Krimpenfort, P., Calafat, J., Niessen, C.M. & Sonnenberg, A. Epithelial detachment due to absence of hemidesmosomes in integrin beta 4 null mice. Nat. Genet. 13, 366–369 (1996).
Ewing, B., Hillier, L., Wendl, M.C. & Green, P. Base-calling of automated sequencer traces using phred. I. Accuracy assessment. Genome Res. 8, 175–185 (1998).
Hentze, M.W. & Kulozik, A.E. A perfect message: RNA surveillance and nonsense-mediated decay. Cell 96, 307–310 (1999).
Acknowledgements
We are grateful to the colleagues who we cite in the text for providing us with various antibodies and reagents. We thank T. Tuschl, S. Pfeffer, E. Bernstein, A. Giraldez and D. Bartel for advice and discussion. We are also grateful to members of the Fuchs lab for their help and critical discussions for the work, and to L. Polak and N. Stokes for assistance in the Rockefeller University Laboratory Animal Research Center. D.O.'C. acknowledges the support of the Irvington Institute for Immunological Research and is their National Genetics Foundation fellow. E.F is an Investigator of the Howard Hughes Medical Institute. This work was supported by the Howard Hughes Medical Institute and in part by a grant from the US National Institutes of Health (AR050452).
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Fig. 1
Preparation of epidermal and HF fractions from E17.5 backskin. (PDF 129 kb)
Supplementary Fig. 2
Epidermal barrier assays. (PDF 60 kb)
Supplementary Fig. 3
Apoptosis in the epidermis and hair follicle of Dicer conditionally null skin. (PDF 1032 kb)
Supplementary Fig. 4
Phenotypic alterations of Dicer null dorsal tongue epithelium and footpad skin. (PDF 124 kb)
Supplementary Table 1
Comprehensive list of the miRNAs cloned in the epidermis and HF of E17.5 embryonic skin. (PDF 65 kb)
Supplementary Table 2
List of primers used in the study. (PDF 39 kb)
Rights and permissions
About this article
Cite this article
Yi, R., O'Carroll, D., Pasolli, H. et al. Morphogenesis in skin is governed by discrete sets of differentially expressed microRNAs. Nat Genet 38, 356–362 (2006). https://doi.org/10.1038/ng1744
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ng1744