Resnik-Docampo, Martin and Koehler, Christopher L. and Clark, Rebecca I. and Schinaman, Joseph M. and Sauer, Vivien and Wong, Daniel M. and Lewis, Sophia and D’Alterio, Cecilia and Walker, David W. and Jones, D. Leanne (2016) 'Tricellular junctions regulate intestinal stem cell behaviour to maintain homeostasis.', Nature cell biology., 19 (1). pp. 52-59.
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.
|Full text:||(AM) Accepted Manuscript|
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|Publisher Web site:||https://doi.org/10.1038/ncb3454|
|Date accepted:||16 November 2016|
|Date deposited:||17 May 2017|
|Date of first online publication:||19 December 2016|
|Date first made open access:||19 June 2017|
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