Drosophila Atg16 promotes enteroendocrine cell differentiation via regulation of intestinal Slit/Robo signaling

Nagy, Péter and Szatmári, Zsuzsanna and Sándor, Gyöngyvér O. and Lippai, Mónika and Hegedűs, Krisztina and Juhász, Gábor (2017) Drosophila Atg16 promotes enteroendocrine cell differentiation via regulation of intestinal Slit/Robo signaling. DEVELOPMENT, 144 (21). pp. 3990-4001. ISSN 0950-1991

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Abstract

Genetic variations of Atg16L1, Slit and Rab19 predispose to the development of inflammatory bowel disease (IBD), but the relationship of these mutations is unclear. Here we show that in Drosophila guts lacking the WD40 domain of Atg16, pre-enteroendocrine cells (pre-EEs) accumulate that fail to differentiate into properly functioning secretory EEs. Mechanistically, loss of Atg16 or its binding partner Rab19 impairs Slit production, which normally inhibits EE generation by activating Robo signaling in stem cells. Importantly, loss of Atg16 or decreased Slit/Robo signaling trigger 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.

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