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Tricellular junctions regulate intestinal stem cell behaviour to maintain homeostasis

Nature Cell Biology volume 19, pages 5259 (2017) | Download Citation


Ageing results in loss of tissue homeostasis across taxa1. In the intestine of Drosophila melanogaster, ageing is correlated with an increase in intestinal stem cell (ISC) proliferation, a block in terminal differentiation of progenitor cells, activation of inflammatory pathways, and increased intestinal permeability2. However, causal relationships between these phenotypes remain unclear. Here, we demonstrate that ageing results in altered localization and expression of septate junction proteins in the posterior midgut, which is quite pronounced in differentiated enterocytes (ECs) at tricellular junctions (TCJs). Acute loss of the TCJ protein Gliotactin (Gli) in ECs results in increased ISC proliferation and a block in differentiation in intestines from young flies, demonstrating that compromised TCJ function is sufficient to alter ISC behaviour in a non-autonomous manner. Blocking the Jun N-terminal kinase signalling pathway is sufficient to suppress changes in ISC behaviour, but has no effect on loss of intestinal barrier function, as a consequence of Gli depletion. Our work demonstrates a pivotal link between TCJs, stem cell behaviour, and intestinal homeostasis and provides insights into causes of age-onset and gastrointestinal diseases.

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The authors thank H. Jasper (The Buck Institute for Research on Aging, USA), V. Auld (University of British Columbia, Canada), J. F. de Celis (CBMSO, Spain), M. Furuse (Kobe University, Japan), the Vienna Drosophila RNAi Center (VDRC), and Bloomington Stock Center for reagents, M. Cilluffo from the Brain Research Institute at UCLA EM core facility, and the Jones and Walker laboratories for comments on the manuscript. In addition, we would like to thank Y. Wu and E. Stefani for their sharing their time, expertise, and STED technology. This work was supported by the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at the University of California, Los Angeles and the Rose Hills Foundation (D.L.J.), and the NIH: AG028092 (D.L.J.), AG040288 (D.L.J. and D.W.W.), AG049157 (D.W.W.), and a training grant that supports the UCLA-Caltech Medical Scientist Training Program, GM08042 (S.L.).

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Author notes

    • Rebecca I. Clark

    Present address: School of Biological and Biomedical Sciences, Durham University, Durham DH1 3LE, UK.


  1. Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, California 90095, USA

    • Martin Resnik-Docampo
    • , Christopher L. Koehler
    • , Vivien Sauer
    • , Daniel M. Wong
    • , Sophia Lewis
    • , Cecilia D’Alterio
    •  & D. Leanne Jones
  2. Department of Integrative Biology and Physiology, University of California, Los Angeles, California 90095, USA

    • Rebecca I. Clark
    • , Joseph M. Schinaman
    •  & David W. Walker
  3. Molecular Biology Institute, University of California, Los Angeles, California 90095, USA

    • David W. Walker
    •  & D. Leanne Jones
  4. Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, California 90095, USA

    • D. Leanne Jones


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M.R.-D. designed, performed and analysed experiments and wrote the manuscript. C.L.K., R.I.C., J.M.S., D.M.W., V.S., S.L. and C.D’A. designed, performed and analysed experiments. D.W.W. designed and analysed experiments. D.L.J. designed and analysed experiments and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to D. Leanne Jones.

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