Drosophila Atg16 promotes enteroendocrine cell differentiation via regulation of intestinal Slit/Robo signaling
Drosophila Atg16 promotes enteroendocrine cell differentiation via regulation of intestinal Slit/Robo signaling
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DOI：
10.1242/dev.147033
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发表时间：
2017-11-01
期刊：
影响因子：
4.6
通讯作者：
Juhasz, Gabor
中科院分区：
文献类型：
--
作者：
Nagy, Peter;Szatmari, Zsuzsanna;Juhasz, Gabor
Atg16l1、Slit2 和 Rab19 的遗传变异易导致炎症性肠病 (IBD) 的发生，但这些突变之间的关系尚不清楚。在这里，我们发现，在缺乏 Atg16 WD40 结构域的果蝇肠道中，前肠内分泌 (pre-EE) 细胞积累，无法分化为正常功能的分泌 EE 细胞。从机制上讲，Atg16 或其结合伴侣 Rab19 的缺失会损害 Slit 的产生，而 Slit 通常通过激活干细胞中的 Robo 信号传导来抑制 EE 细胞的生成。重要的是，Atg16 的缺失或 Slit/Robo 信号传导的减少会引发肠道炎症反应。令人惊讶的是，对 Rab19 和域特异性 Atg16 突变体的分析表明，它们的干细胞生态位调节功能独立于自噬。我们的研究揭示了这些不同基因的突变如何导致炎症性肠病。
Genetic variations of Atg16l1, Slit2 and Rab19 predispose to the development of inflammatory bowel disease (IBD), but the relationship between these mutations is unclear. Here we show that in Drosophila guts lacking the WD40 domain of Atg16, pre-enteroendocrine (pre-EE) cells accumulate that fail to differentiate into properly functioning secretory EE cells. Mechanistically, loss of Atg16 or its binding partner Rab19 impairs Slit production, which normally inhibits EE cell generation by activating Robo signaling in stem cells. Importantly, loss of Atg16 or decreased Slit/Robo signaling triggers an intestinal inflammatory response. Surprisingly, analysis of Rab19 and domain-specific Atg16 mutants indicates that their stem cell niche regulatory function is independent of autophagy. Our study reveals how mutations in these different genes may contribute to IBD.