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miRNA-mediated feedback inhibition of JAK/STAT morphogen signalling establishes a cell fate threshold

Nature Cell Biology volume 13, pages 1062–1069 (2011)Cite this article

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Abstract

Patterns of cell fates generated by morphogens are critically important for normal development; however, the mechanisms by which graded morphogen signals are converted into all-or-none cell fate responses are incompletely understood. In the Drosophila ovary, high and sustained levels of the secreted morphogen Unpaired (Upd) specify the migratory border-cell population by activating the signal transducer and activator of transcription1,2 (STAT). A lower or transient level of STAT activity specifies a non-migratory population of follicle cells3,4. Here we identify miR-279 as a component of a feedback pathway that further dampens the response in cells with low levels of JAK/STAT activity. miR-279 directly repressed STAT, and loss of miR-279 mimicked STAT gain-of-function or loss of Apontic (Apt), a known feedback inhibitor of STAT. Apt was essential for miR-279 expression in non-migratory follicle cells, whereas another STAT target, Ken and Barbie (Ken), downregulated miR-279 in border cells. Mathematical modelling and simulations of this regulatory circuit including miR-279, Apt and Ken supported key roles for miR-279 and Apt in generating threshold responses to the Upd gradient.

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Figure 1: STAT is a target of miR-279.
Figure 2: Loss-of-function of miR-279 phenocopies gain-of-function of STAT.
Figure 3: STAT is a critical target of miR-279 in vivo.
Figure 4: Two STAT targets, Apt and Ken, feedback through miR-279.
Figure 5: A model of the gene regulatory circuit required to specify non-migratory anterior follicle cell and migratory border-cell fate.

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Acknowledgements

This work was supported by NIH grant GM46425 to D.J.M. W.H.Y. was supported by a fellowship from the Korea Science and Engineering Foundation (KOSEF) and the H.A. and Mary K. Chapman Young Investigator Fellowship. We acknowledge A. H. McDonald and B. Steiner for technical assistance. We thank J. S. Kang for data illustration. We thank M. Issigonis for helpful discussion. We thank present and past members of the D.J.M. and C. Montell laboratories for helpful discussion and comments. Flybase and the Bloomington Drosophila Stock Center provided critical information and reagents for this study.

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Authors and Affiliations

  1. Department of Biological Chemistry, Center for Cell Dynamics, Johns Hopkins University School of Medicine, 855 North Wolfe Street, Baltimore, Maryland 21205, Suite 450, USA

    Wan Hee Yoon & Denise J. Montell

  2. Max-Planck-Institut für Entwicklungsbiologie, Spemannstrasse 35, D-72076 Tübingen, Germany

    Hans Meinhardt

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  1. Wan Hee Yoon
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W.H.Y. planned the experimental design, conducted the experiments and analysed data. H.M. developed and tested the mathematical model. D.J.M. conceived of the project, participated in experimental design, discussions of results and interpretations, and wrote the manuscript.

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Correspondence to Denise J. Montell.

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Yoon, W., Meinhardt, H. & Montell, D. miRNA-mediated feedback inhibition of JAK/STAT morphogen signalling establishes a cell fate threshold. Nat Cell Biol 13, 1062–1069 (2011). https://doi.org/10.1038/ncb2316

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