Nagy Péter, Szatmári Zsuzsanna, Sándor Gyöngyvér O, Lippai Mónika, Hegedűs Krisztina, Juhász Gábor
Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University, Pázmány s. 1/C, Budapest, H-1117 Hungary.
Department of Anatomy, Cell and Developmental Biology, Eötvös Loránd University, Pázmány s. 1/C, Budapest, H-1117 Hungary
Development. 2017 Nov 1;144(21):3990-4001. doi: 10.1242/dev.147033. Epub 2017 Oct 5.
Genetic variations of , and predispose to the development of inflammatory bowel disease (IBD), but the relationship between these mutations is unclear. Here we show that in 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 and domain-specific 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.
Atg16、Rab19和Robo的基因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，我们表明，在缺乏Atg16 WD40结构域的肠道中，前肠内分泌（pre-EE）细胞会积累，无法分化为功能正常的分泌性EE细胞。从机制上讲，Atg16或其结合伙伴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信号来抑制EE细胞的生成。重要的是，Atg16的缺失或Slit/Robo信号的减少会引发肠道炎症反应。令人惊讶的是，对Rab19和结构域特异性Robo突变体的分析表明，它们的干细胞微环境调节功能独立于自噬。我们的研究揭示了这些不同基因中的突变如何可能导致IBD。
