microRNA-184 Induces a Commitment Switch to Epidermal Differentiation

Sara Nagosa, Friederike Leesch, Daria Putin, Swarnabh Bhattacharya, Anna Altshuler, Laura Serror, Aya Amitai-Lange, Waseem Nasser, Edith Aberdam, Matthieu Rouleau, Sudhir G. Tattikota, Matthew Poy, Daniel Aberdam, Ruby Shalom-Feuerstein

Research output: Contribution to journalArticle

Abstract

miR-184 is a highly evolutionary conserved microRNA (miRNA) from fly to human. The importance of miR-184 was underscored by the discovery that point mutations in miR-184 gene led to corneal/lens blinding disease. However, miR-184-related function in vivo remained unclear. Here, we report that the miR-184 knockout mouse model displayed increased p63 expression in line with epidermal hyperplasia, while forced expression of miR-184 by stem/progenitor cells enhanced the Notch pathway and induced epidermal hypoplasia. In line, miR-184 reduced clonogenicity and accelerated differentiation of human epidermal cells. We showed that by directly repressing cytokeratin 15 (K15) and FIH1, miR-184 induces Notch activation and epidermal differentiation. The disease-causing miR-184C57U mutant failed to repress K15 and FIH1 and to induce Notch activation, suggesting a loss-of-function mechanism. Altogether, we propose that, by targeting K15 and FIH1, miR-184 regulates the transition from proliferation to early differentiation, while mis-expression or mutation in miR-184 results in impaired homeostasis. Using new genetic mouse models and study of human epidermal cells, Nagosa et al. show that miR-184 regulates epidermal proliferation and commitment to differentiation. The authors discovered that miR-184 directly represses K15 and FIH1, which are important for the maintenance of stemness phenotype.

Original languageEnglish (US)
Pages (from-to)1991-2004
Number of pages14
JournalStem Cell Reports
Volume9
Issue number6
DOIs
StatePublished - Dec 12 2017
Externally publishedYes

Keywords

  • cornea
  • epidermis
  • FIH1
  • hair follicle
  • K15
  • microRNA
  • miR-184
  • miRNA-184
  • notch
  • stem cells

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology

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  • Cite this

    Nagosa, S., Leesch, F., Putin, D., Bhattacharya, S., Altshuler, A., Serror, L., Amitai-Lange, A., Nasser, W., Aberdam, E., Rouleau, M., Tattikota, S. G., Poy, M., Aberdam, D., & Shalom-Feuerstein, R. (2017). microRNA-184 Induces a Commitment Switch to Epidermal Differentiation. Stem Cell Reports, 9(6), 1991-2004. https://doi.org/10.1016/j.stemcr.2017.10.030