Tricellular junctions regulate intestinal stem cell behaviour to maintain homeostasis.
Tricellular junctions regulate intestinal stem cell behaviour to maintain homeostasis.
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DOI：
10.1038/ncb3454
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发表时间：
2017-01
影响因子：
21.3
通讯作者：
Jones DL
中科院分区：
文献类型：
--
作者：
Resnik-Docampo M;Koehler CL;Clark RI;Schinaman JM;Sauer V;Wong DM;Lewis S;D'Alterio C;Walker DW;Jones DL
衰老导致整个类群的组织稳态丧失。在果蝇肠道中，衰老与肠道干细胞（ISC）增殖增加、祖细胞终末分化受阻、炎症途径激活和肠道通透性增加相关。然而，这些表型之间的因果关系仍不清楚。在这里，我们证明衰老会导致中肠后部隔膜连接蛋白的定位和表达发生改变，这在三细胞连接处（TCJ）的分化肠上皮细胞（EC）中非常明显。 EC 中 TCJ 蛋白 Gliotactin (Gli) 的急性缺失会导致 ISC 增殖增加，并阻碍幼果蝇肠道分化，这表明 TCJ 功能受损足以以非自主方式改变 ISC 行为。阻断 Jun N 末端激酶信号通路足以抑制 ISC 行为的变化，但对 Gli 耗竭导致的肠道屏障功能丧失没有影响。我们的工作证明了 TCJ、干细胞行为和肠道稳态之间的关键联系，并提供了对衰老和胃肠道疾病的原因的见解。
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.
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