Tricellular junctions regulate intestinal stem cell behaviour to maintain homeostasis

Resnik-Docampo, Martin; Koehler, Christopher L.; Clark, Rebecca I.; Schinaman, Joseph M.; Sauer, Vivien; Wong, Daniel M.; Lewis, Sophia; D’Alterio, Cecilia; Walker, David W.; Jones, D. Leanne

Abstract

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.

Citation

Resnik-Docampo, M., Koehler, C. L., Clark, R. I., Schinaman, J. M., Sauer, V., Wong, D. M., …Jones, D. L. (2016). Tricellular junctions regulate intestinal stem cell behaviour to maintain homeostasis. Nature Cell Biology, 19(1), 52-59. https://doi.org/10.1038/ncb3454

• Journal Article Type: Article
• Acceptance Date: Nov 16, 2016
• Online Publication Date: Dec 19, 2016
• Publication Date: Dec 19, 2016
• Deposit Date: May 16, 2017
• Publicly Available Date: Jun 19, 2017
• Journal: Nature Cell Biology
• Print ISSN: 1465-7392
• Electronic ISSN: 1476-4679
• Publisher: Nature Research
• Peer Reviewed: Peer Reviewed
• Volume: 19
• Issue: 1
• Pages: 52-59
• DOI: https://doi.org/10.1038/ncb3454
• Public URL: https://durham-repository.worktribe.com/output/1378961