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Drosophila Src regulates anisotropic apical surface growth to control epithelial tube size

Nature Cell Biology volume 14, pages 518–525 (2012)Cite this article

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Abstract

Networks of epithelial and endothelial tubes are essential for the function of organs such as the lung, kidney and vascular system. The sizes and shapes of these tubes are highly regulated to match their individual functions. Defects in tube size can cause debilitating diseases such as polycystic kidney disease and ischaemia1,2. It is therefore critical to understand how tube dimensions are regulated. Here we identify the tyrosine kinase Src as an instructive regulator of epithelial-tube length in the Drosophila tracheal system. Loss-of-function Src42 mutations shorten tracheal tubes, whereas Src42 overexpression elongates them. Surprisingly, Src42 acts distinctly from known tube-size pathways and regulates both the amount of apical surface growth and, with the conserved formin dDaam, the direction of growth. Quantitative three-dimensional image analysis reveals that Src42- and dDaam-mutant tracheal cells expand more in the circumferential than the axial dimension, resulting in tubes that are shorter in length—but larger in diameter—than wild-type tubes. Thus, Src42 and dDaam control tube dimensions by regulating the direction of anisotropic growth, a mechanism that has not previously been described.

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Figure 1: Src42 acts autonomously to control tracheal tube length.
Figure 2: Src42 acts independently of the aECM-based tube-size-control pathway.
Figure 3: Src42 is required for orienting anisotropic apical surface expansion along the longitudinal axis of tracheal tubes.
Figure 4: dDaam is required for tracheal-tube elongation.
Figure 5: dDaam functions with Src42 to control tube size.

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Acknowledgements

We thank M. Zeeb and E. Lammert for sharing unpublished results and comments on the manuscript, R. Carthew, S. Hilgenfeldt and A. Dudley for discussions, Bill Russin and the Northwestern Biological Imaging Facility for imaging support, S. Hayashi, A. O’Reilly, T. Xu, the Bloomington Stock Center and the Developmental Studies Hybridoma Bank for fly stocks and reagents, M. Singh for technical advice and R. Robbins, T. Helenius and T. Krupinski for comments on the manuscript. This work was supported by a predoctoral fellowship from the National Institutes of Health (NIH) Cellular and Molecular Basis of Disease training grant (T32 GM008061 to K.S.N.), a Malkin Scholar Award (to K.S.N.), an Achievement Rewards for College Scientists (ARCS) Award (to K.S.N.), a grant from the Northwestern University Alumni Association (to G.J.B.), NIH grant P50 GM 071508, principal investigator D. Botstein (Z.K. and M.K.), and Hungarian Scientific Research Fund (OTKA) grant K 82039 (to J.M.).

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Author notes

  1. Zia Khan & Matthias Kaschube

    Present address: Present addresses: Department of Human Genetics, University of Chicago, Chicago, Illinois 60637, USA (Z.K.); Frankfurt Institute for Advanced Studies and Department of Computer Science and Mathematics, Johann Wolfgang Goethe University, Frankfurt am Main 60438, Germany (M.K.),

Authors and Affiliations

  1. Department of Molecular Biosciences and Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Evanston, Illinois 60208, USA

    Kevin S. Nelson & Greg J. Beitel

  2. Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, New Jersey 08544, USA

    Zia Khan & Matthias Kaschube

  3. Department of Computer Science, Princeton University, Princeton, New Jersey 08540, USA

    Zia Khan

  4. Institute of Genetics, Biological Research Centre, Hungarian Academy of Sciences, Temesvari krt. 62, Szeged 6726, Hungary

    Imre Molnár & József Mihály

  5. Department of Physics, Princeton University, Princeton, New Jersey 08544, USA

    Matthias Kaschube

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Contributions

K.S.N. carried out all experiments, Z.K. generated and analysed individual dorsal-trunk cell quantifications, I.M. generated the UAS–Flag–dDaam construct and the dDaam antibody, K.S.N., Z.K., M.K. and G.J.B. designed and interpreted the experiments and K.S.N., Z.K., J.M., M.K. and G.J.B. wrote the paper.

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Correspondence to Greg J. Beitel.

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Nelson, K., Khan, Z., Molnár, I. et al. Drosophila Src regulates anisotropic apical surface growth to control epithelial tube size. Nat Cell Biol 14, 518–525 (2012). https://doi.org/10.1038/ncb2467

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