title: Tricellular junctions regulate intestinal stem cell behaviour to maintain homeostasis.
abstract: Ageing results in loss of tissue homeostasis across taxa. 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. 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.
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, California 90095, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Resnik-Docampo
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, California 90095, USA.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Koehler
authors.affiliation: Department of Integrative Biology and Physiology, University of California, Los Angeles, California 90095, USA.
authors.forename: Rebecca I
authors.initials: RI
authors.lastname: Clark
authors.affiliation: Department of Integrative Biology and Physiology, University of California, Los Angeles, California 90095, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Schinaman
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, California 90095, USA.
authors.forename: Vivien
authors.initials: V
authors.lastname: Sauer
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, California 90095, USA.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Wong
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, California 90095, USA.
authors.forename: Sophia
authors.initials: S
authors.lastname: Lewis
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, California 90095, USA.
authors.forename: Cecilia
authors.initials: C
authors.lastname: D'Alterio
authors.affiliation: Department of Integrative Biology and Physiology, University of California, Los Angeles, California 90095, USA.|Molecular Biology Institute, University of California, Los Angeles, California 90095, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Walker
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, California 90095, USA.|Molecular Biology Institute, University of California, Los Angeles, California 90095, USA.|Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, California 90095, USA.
authors.forename: D Leanne
authors.initials: DL
authors.lastname: Jones
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D029721:Drosophila Proteins / Q000378:metabolism; D004331:Drosophila melanogaster / Q000166:cytology* / Q000648:ultrastructure; D020895:Enterocytes / Q000166:cytology / Q000648:ultrastructure; D006706:Homeostasis; D007365:Intercellular Junctions / Q000378:metabolism*; D007422:Intestines / Q000166:cytology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C094064:gliotactin; D048031:JNK Mitogen-Activated Protein Kinases