Strang Laboratory of Apoptosis and Cancer Biology, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
Strang Laboratory of Apoptosis and Cancer Biology, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA
Development. 2019 Mar 15;146(6):dev169284. doi: 10.1242/dev.169284.
Self-renewal of intestinal stem cells is controlled by Wingless/Wnt-β catenin signaling in both and mammals. As Axin is a rate-limiting factor in Wingless signaling, its regulation is essential. Iduna is an evolutionarily conserved ubiquitin E3 ligase that has been identified as a crucial regulator for degradation of ADP-ribosylated Axin and, thus, of Wnt/β-catenin signaling. However, its physiological significance remains to be demonstrated. Here, we generated loss-of-function mutants of to investigate its physiological role in Genetic depletion of causes the accumulation of both Tankyrase and Axin. Increase of Axin protein in enterocytes non-autonomously enhanced stem cell divisions in the midgut. Enterocytes secreted Unpaired proteins and thereby stimulated the activity of the JAK-STAT pathway in intestinal stem cells. A decrease in gene expression suppressed the over-proliferation of stem cells and restored their numbers to normal levels in mutants. These findings suggest that Iduna-mediated regulation of Axin proteolysis is essential for tissue homeostasis in the midgut.
肠干细胞的自我更新由 Wingless/Wnt-β-catenin 信号在 和哺乳动物中控制。由于 Axin 是 Wingless 信号的限速因子，因此其调节至关重要。Iduna 是一种进化上保守的泛素 E3 连接酶，已被确定为 ADP-ribosylated Axin 降解和 Wnt/β-catenin 信号的关键调节剂。然而，其生理意义仍有待证明。在这里，我们生成了 的功能缺失突变体，以研究其在 中的生理作用。遗传耗尽 会导致 Tankyrase 和 Axin 的积累。肠细胞中非自主地增加 Axin 蛋白会增强 中肠干细胞的分裂。肠细胞分泌 Unpaired 蛋白，从而刺激肠干细胞中 JAK-STAT 途径的活性。减少 基因表达会抑制干细胞的过度增殖，并将其数量恢复到 突变体的正常水平。这些发现表明，Iduna 介导的 Axin 蛋白水解调节对于 中肠的组织稳态至关重要。
