4.8 Article

Tricellular junctions regulate intestinal stem cell behaviour to maintain homeostasis

Journal

NATURE CELL BIOLOGY
Volume 19, Issue 1, Pages 52-59

Publisher

NATURE PUBLISHING GROUP
DOI: 10.1038/ncb3454

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Funding

  1. Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at the University of California, Los Angeles
  2. Rose Hills Foundation
  3. NIH [AG028092, AG040288, AG049157]
  4. UCLA-Caltech Medical Scientist Training Program [GM08042]
  5. NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK105442] Funding Source: NIH RePORTER
  6. NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [T32GM008042] Funding Source: NIH RePORTER
  7. NATIONAL INSTITUTE ON AGING [R01AG028092, R01AG049157, R01AG040288] Funding Source: NIH RePORTER

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Ageing results in loss of tissue homeostasis across taxa(1). 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 permeability(2). 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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