1. Developmental Biology
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Localized JNK signaling regulates organ size during development

  1. Helen Rankin Willsey
  2. Xiaoyan Zheng
  3. José Carlos Pastor-Pareja
  4. A Jeremy Willsey
  5. Philip A Beachy
  6. Tian Xu  Is a corresponding author
  1. Howard Hughes Medical Institute, Yale University School of Medicine, United States
  2. The George Washington University, United States
  3. Tsinghua University, China
  4. University of California, San Francisco, United States
Research Article
  • Cited 18
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Cite this article as: eLife 2016;5:e11491 doi: 10.7554/eLife.11491

Abstract

A fundamental question of biology is what determines organ size. Despite demonstrations that factors within organs determine their sizes, intrinsic size control mechanisms remain elusive. Here we show that Drosophila wing size is regulated by JNK signaling during development. JNK is active in a stripe along the center of developing wings, and modulating JNK signaling within this stripe changes organ size. This JNK stripe influences proliferation in a non-canonical, Jun-independent manner by inhibiting the Hippo pathway. Localized JNK activity is established by Hedgehog signaling, where Ci elevates dTRAF1 expression. As the dTRAF1 homolog, TRAF4, is amplified in numerous cancers, these findings provide a new mechanism for how the Hedgehog pathway could contribute to tumorigenesis, and, more importantly, provides a new strategy for cancer therapies. Finally, modulation of JNK signaling centers in developing antennae and legs changes their sizes, suggesting a more generalizable role for JNK signaling in developmental organ size control.

Article and author information

Author details

  1. Helen Rankin Willsey

    Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Xiaoyan Zheng

    Department of Anatomy and Regenerative Biology, School of Medicine and Health Sciences, The George Washington University, Washington, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. José Carlos Pastor-Pareja

    School of Life Sciences, Tsinghua University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  4. A Jeremy Willsey

    Department of Psychiatry, University of California, San Francisco, San Francisco, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Philip A Beachy

    Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, Stanford, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Tian Xu

    Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, United States
    For correspondence
    tian.xu@yale.edu
    Competing interests
    The authors declare that no competing interests exist.

Reviewing Editor

  1. Helen McNeill, The Samuel Lunenfeld Research Institute, Canada

Publication history

  1. Received: September 22, 2015
  2. Accepted: March 12, 2016
  3. Accepted Manuscript published: March 14, 2016 (version 1)
  4. Accepted Manuscript updated: March 22, 2016 (version 2)
  5. Version of Record published: April 27, 2016 (version 3)

Copyright

© 2016, Willsey et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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Further reading

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    In emerging epithelial tissues, cells undergo dramatic rearrangements to promote tissue shape changes. Dividing cells remain interconnected via transient cytokinetic bridges. Bridges are cleaved during abscission and currently, the consequences of disrupting abscission in developing epithelia are not well understood. We show that the Rab GTPase Rab25 localizes near cytokinetic midbodies and likely coordinates abscission through endomembrane trafficking in the epithelium of the zebrafish gastrula during epiboly. In maternal-zygotic Rab25a and Rab25b mutant embryos, morphogenic activity tears open persistent apical cytokinetic bridges that failed to undergo timely abscission. Cytokinesis defects result in anisotropic cell morphologies that are associated with a reduction of contractile actomyosin networks. This slows cell rearrangements and alters the viscoelastic responses of the tissue, all of which likely contribute to delayed epiboly. We present a model in which Rab25 trafficking coordinates cytokinetic bridge abscission and cortical actin density, impacting local cell shape changes and tissue-scale forces.

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    Actomyosin contractility is regulated by Rho-GTP in cell migration, cytokinesis and morphogenesis in embryo development. Whereas Rho activation by Rho-GTP exchange factor (GEF), RhoGEF2 is well known in actomyosin contractility during cytokinesis at the base of invaginating membranes in Drosophila cellularization, Rho inhibition by RhoGTPase activating proteins (GAP) remains to be studied. We have found that the RhoGAP, GRAF inhibits actomyosin contractility during cellularization. GRAF is enriched at the cleavage furrow tip during actomyosin assembly and initiation of ring constriction. Graf depletion shows increased Rho-GTP, increased Myosin II and ring hyper constriction dependent upon the loss of the RhoGTPase domain. GRAF and RhoGEF2 are present in a balance for appropriate activation of actomyosin ring constriction. RhoGEF2 depletion and abrogation of Myosin II activation in Rho Kinase mutants suppresses the Graf hyper constriction defect. Therefore, GRAF recruitment restricts Rho-GTP levels in a spatiotemporal manner for inhibiting actomyosin contractility during cellularization.