Tricellular junctions regulate intestinal stem cell behaviour to maintain homeostasis

Developers

Martin Resnik-Docampo, Christopher L. Koehler, David W. Walker, D. Leanne Jones, etc.

Description of the technology

Ageing results in loss of tissue homeostasis across taxa. Particularly, in the intestine of Drosophila melanogaster, ageing is correlated with an increase in intestinal stem cell proliferation, a block in terminal differentiation of progenitor cells, activation of inflammatory pathways, and increased intestinal permeability. However, causal relationships between these phenotypes remain unclear.

The authors demonstrated that ageing results in altered localization and expression of junction proteins in the posterior midgut of Drosophila melanogaster, which is quite pronounced in differentiated enterocytes at tricellular junctions. Acute loss of the tricellular junction protein Gliotactin in enterocytes results in increased intestinal stem cell proliferation and a block in differentiation in intestines from young flies, demonstrating that compromised tricellular junction function is sufficient to alter intestinal stem cell behaviour in a non-autonomous manner. In turn, blocking the Jun N-terminal kinase signalling pathway is sufficient to suppress changes in intestinal stem cell behaviour, but has no effect on loss of intestinal barrier function, as a consequence of Gliotactin depletion. This study demonstrates a pivotal link between tricellular junctions, stem cell behaviour, and intestinal homeostasis and provides insights into causes of age-onset and gastrointestinal diseases.

Thus, the investigation of specific tricellular junction function, localization and expression of junction proteins can serve as a technology, which helps to reveal the age-associated and degenerative diseases

Practical application

The study of age-dependent remodelling of epithelial junctions, being the core of this technology, can reveal age-related changes in stem cell behaviour. Besides, it can serve as a diagnostic technique, because epithelial junction remodelling could be a driver of a host of intestinal diseases, including colon cancer.

Furthermore, if age-related changes in tricellular junctions also occur within tissues in which low or no cell turnover takes place, loss of barrier function could be a substantial contributing factor to age-onset or degenerative diseases in tissues such as the nervous system, ear, or the kidney. Thus, mentioned changes can be used for diagnostics and study of these diseases.

Laboratories

• Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles (USA)
• Department of Integrative Biology and Physiology, University of California, Los Angeles (USA)
• Molecular Biology Institute, University of California, Los Angeles (USA)
• Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles (USA)

Links

Publications

• Resnik-Docampo, M. et al. «Tricellular junctions regulate intestinal stem cell behaviour to maintain homeostasis." 19 Nature Cell Biology, (2017): 52–59.
• Jones, D. L. & Rando, T. A. «Emerging models and paradigms for stem cell ageing." 13 Nat. Cell Biol. (2011): 506–512.
• Rera, M., Clark, R. I. & Walker, D. W. «Intestinal barrier dysfunction links metabolic and inflammatory markers of aging to death in Drosophila." 109 Proc. Natl Acad. Sci. USA, (2012): 21528–21533.