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Morphogenesis in skin is governed by discrete sets of differentially expressed microRNAs

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.

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Figure 1: Differential expression patterns of representative miRNAs in the epidermis and hair follicle.
Figure 2: Conditional ablation of Dicer1 and quantitative loss of miRNAs in skin.
Figure 3: Phenotypic and morphological alterations accompanied by signs of apoptosis in Dicer1 conditional null skin.
Figure 4: Morphological characterization of evaginations of hair follicles in Dicer1 conditional knockout skin.
Figure 5: Derivation of the hair follicle cysts within Dicer1-null epidermis.

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References

  1. Bartel, D.P. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297 (2004).

    Article  CAS  Google Scholar 

  2. Kim, V.N. MicroRNA biogenesis: coordinated cropping and dicing. Nat. Rev. Mol. Cell Biol. 6, 376–385 (2005).

    Article  CAS  Google Scholar 

  3. Chen, C.Z., Li, L., Lodish, H.F. & Bartel, D.P. MicroRNAs modulate hematopoietic lineage differentiation. Science 303, 83–86 (2004).

    Article  CAS  Google Scholar 

  4. Poy, M.N. et al. A pancreatic islet-specific microRNA regulates insulin secretion. Nature 432, 226–230 (2004).

    Article  CAS  Google Scholar 

  5. He, L. et al. A microRNA polycistron as a potential human oncogene. Nature 435, 828–833 (2005).

    Article  CAS  Google Scholar 

  6. 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).

    Article  CAS  Google Scholar 

  7. Wienholds, E. & Plasterk, R.H. MicroRNA function in animal development. FEBS Lett. 579, 5911–5922 (2005).

    Article  CAS  Google Scholar 

  8. Zhao, Y., Samal, E. & Srivastava, D. Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis. Nature 436, 214–220 (2005).

    Article  CAS  Google Scholar 

  9. Rendl, M., Lewis, L. & Fuchs, E. Molecular dissection of mesenchymal-epithelial interactions in the hair follicle. PLoS Biol. 3, e331 (2005).

    Article  Google Scholar 

  10. Chen, P.Y. et al. The developmental miRNA profiles of zebrafish as determined by small RNA cloning. Genes Dev. 19, 1288–1293 (2005).

    Article  CAS  Google Scholar 

  11. Griffiths-Jones, S. The microRNA Registry. Nucleic Acids Res. 32, D109–D111 (2004).

    Article  CAS  Google Scholar 

  12. Fukagawa, T. et al. Dicer is essential for formation of the heterochromatin structure in vertebrate cells. Nat. Cell Biol. 6, 784–791 (2004).

    Article  CAS  Google Scholar 

  13. 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).

    Article  CAS  Google Scholar 

  14. 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).

    Article  CAS  Google Scholar 

  15. Bernstein, E. et al. Dicer is essential for mouse development. Nat. Genet. 35, 215–217 (2003).

    Article  CAS  Google Scholar 

  16. 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).

    Article  CAS  Google Scholar 

  17. Muljo, S.A. et al. Aberrant T cell differentiation in the absence of Dicer. J. Exp. Med. 202, 261–269 (2005).

    Article  CAS  Google Scholar 

  18. 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).

    Article  CAS  Google Scholar 

  19. Kanellopoulou, C. et al. Dicer-deficient mouse embryonic stem cells are defective in differentiation and centromeric silencing. Genes Dev. 19, 489–501 (2005).

    Article  CAS  Google Scholar 

  20. 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).

    Article  CAS  Google Scholar 

  21. Kaufman, C.K. et al. GATA-3: an unexpected regulator of cell lineage determination in skin. Genes Dev. 17, 2108–2122 (2003).

    Article  CAS  Google Scholar 

  22. 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).

    Article  CAS  Google Scholar 

  23. Tumbar, T. et al. Defining the epithelial stem cell niche in skin. Science 303, 359–363 (2004).

    Article  CAS  Google Scholar 

  24. 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).

    Article  CAS  Google Scholar 

  25. 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).

    Article  CAS  Google Scholar 

  26. 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).

    Article  CAS  Google Scholar 

  27. 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).

    Article  CAS  Google Scholar 

  28. 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).

    Article  CAS  Google Scholar 

  29. Hentze, M.W. & Kulozik, A.E. A perfect message: RNA surveillance and nonsense-mediated decay. Cell 96, 307–310 (1999).

    Article  CAS  Google Scholar 

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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).

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Correspondence to Alexander Tarakhovsky or Elaine Fuchs.

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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)

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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

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