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MicroRNA MiR-17 retards tissue growth and represses fibronectin expression

Nature Cell Biology volume 11, pages 1031–1038 (2009)Cite this article

Abstract

MicroRNAs (miRNAs) are single-stranded regulatory RNAs, frequently expressed as clusters. Previous studies have demonstrated that the six-miRNA cluster miR-17∼92 has important roles in tissue development and cancers. However, the precise role of each miRNA in the cluster is unknown. Here we show that overexpression of miR-17 results in decreased cell adhesion, migration and proliferation. Transgenic mice overexpressing miR-17 showed overall growth retardation, smaller organs and greatly reduced haematopoietic cell lineages. We found that fibronectin and the fibronectin type-III domain containing 3A (FNDC3A) are two targets that have their expression repressed by miR-17, both in vitro and in transgenic mice. Several lines of evidence support the notion that miR-17 causes cellular defects through its repression of fibronectin expression. Our single miRNA expression assay may be evolved to allow the manipulation of individual miRNA functions in vitro and in vivo. We anticipate that this could serve as a model for studying gene regulation by miRNAs in the development of gene therapy.

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Figure 1: Expression of miR-17 affects cell activities.
Figure 2: Retarded growth of bodies and organs in transgenic mice expressing miR-17.
Figure 3: Pathological analysis of transgenic mice expressing miR-17.
Figure 4: Targeting analysis of miR-17 in vitro.
Figure 5: Confirmation of target expression in vivo.

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Acknowledgements

We thank J. Ma for assistance in real-time PCR experiments, G. Knowles for flow cytometry analysis at the Core Facilities of Sunnybrook Research Institute, S. Gatchell and K. Green for the generation and maintenance of transgenic mice at UWO, D. Wei for technical assistance in molecular cloning, and J. Yang for editing the manuscript. This work was supported by a grant (NA 6282) and a Career Investigator Award (CI 5958) from Heart and Stroke Foundation of Ontario to B.B.Y. and a China-Canada Joint Health Research Grant (from Canadian Institutes of Health Research and the National Natural Science Foundation of China to B.B.Y. and Y.Z.). D.Y.L. is the recipient of a Canada Graduate Scholarship.

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Author notes

  1. Siu-Pok Yee

    Present address: Current address: Department of Genetics and Developmental Biology, University of Connecticut Health Center, Farmington, CT 06030, USA.,

  2. Sze Wan Shan, Daniel Y. Lee and Zhaoqun Deng: These authors contributed equally to this work.

Authors and Affiliations

  1. Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario, Canada

    Sze Wan Shan, Daniel Y. Lee, Zhaoqun Deng, Tatiana Shatseva, Zina Jeyapalan, William W. Du, Vinayakumar Siragam & Burton B. Yang

  2. Life Science Division, Graduate School at Shenzhen, Building L, Tsinghua Campus, University Town, Shenzhen, China

    Yaou Zhang

  3. Lawson Health Research Institute, University of Western Ontario, 375 South Street, London, Ontario, Canada

    Jim W. Xuan

  4. Departments of Oncology and Biochemistry, University of Western Ontario, 375 South Street, London, Ontario, Canada

    Siu-Pok Yee

  5. Department of Laboratory Medicine and Pathobiology, University of Toronto, 100 College Street, Toronto, Ontario, Canada

    Sze Wan Shan, Daniel Y. Lee, Zina Jeyapalan & Burton B. Yang

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Contributions

S.W.S. generated expression constructs, performed the in vitro cell activity assays including western blot analysis, RT-PCR and northern blots, and was involved in writing the related method sections; D.Y.L. performed genotype analysis, RT-PCR, northern blots, organized/prepared animal samples, assisted in B-cell FACS analysis, and was involved in tissue collection and in writing the related method sections; Z.D. was involved in organizing animal samples, performed RT-PCR, real-time PCR, and RNase-protection assays; T.S. designed bone marrow and lymph node B-cell experiments, performed bone marrow B-cell FACS analysis and immunohistochemistry, and was involved in writing the related methods; Z.J. performed luciferase activity assays; W.W.D. was involved in western blot analysis; Y.Z. provided analytical tools; J.W.X. was involved in mouse dissection analysis; S.P.Y. oversaw the generation of transgenic mice and was involved in writing the methods; V.S. designed and performed spleen B-cell experiments; B.B.Y. directed the research, designed and coordinated the project, analysed the data, and wrote the manuscript.

Corresponding author

Correspondence to Burton B. Yang.

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Shan, S., Lee, D., Deng, Z. et al. MicroRNA MiR-17 retards tissue growth and represses fibronectin expression. Nat Cell Biol 11, 1031–1038 (2009). https://doi.org/10.1038/ncb1917

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