Distinct ATOH1 and Neurog3 requirements define tuft cells as a new secretory cell type in the intestinal epithelium. J Cell Biol

CNRS UMR5203, Montpellier F-34094, France.
The Journal of Cell Biology (Impact Factor: 9.83). 03/2011; 192(5):767-80. DOI: 10.1083/jcb.201010127
Source: PubMed


The unique morphology of tuft cells was first revealed by electron microscopy analyses in several endoderm-derived epithelia. Here, we explore the relationship of these cells with the other cell types of the intestinal epithelium and describe the first marker signature allowing their unambiguous identification. We demonstrate that although mature tuft cells express DCLK1, a putative marker of quiescent stem cells, they are post-mitotic, short lived, derive from Lgr5-expressing epithelial stem cells, and are found in mouse and human tumors. We show that whereas the ATOH1/MATH1 transcription factor is essential for their differentiation, Neurog3, SOX9, GFI1, and SPDEF are dispensable, which distinguishes these cells from enteroendocrine, Paneth, and goblet cells, and raises from three to four the number of secretory cell types in the intestinal epithelium. Moreover, we show that tuft cells are the main source of endogenous intestinal opioids and are the only epithelial cells that express cyclooxygenase enzymes, suggesting important roles for these cells in the intestinal epithelium physiopathology.

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    • "Tuft cells originate from poorly characterized tuft cell progenitors, are enriched in acetylated α-tubulin, and show characteristic microtubule and actin bundles located at the cell apex exposed to the luminal environment (Gerbe et al., 2011, 2012). They are distinct from intestinal secretory cells, as transcription factors such as Neurog3, Sox9, and Spdef are dispensable for their generation (Gerbe et al., 2011; Bjerknes et al., 2012). Tuft cells specifically express Doublecortin-like kinase 1 (Dclk1; also referred to as Dcamkl-1) as well as the transcription factor Gfi1B (Bjerknes et al., 2012; Gerbe et al., 2012). "
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    ABSTRACT: Tumor initiation in the intestine can rapidly occur from Lgr5(+) crypt columnar stem cells. Dclk1 is a marker of differentiated Tuft cells and, when coexpressed with Lgr5, also marks intestinal cancer stem cells. Here, we show that Elp3, the catalytic subunit of the Elongator complex, is required for Wnt-driven intestinal tumor initiation and radiation-induced regeneration by maintaining a subpool of Lgr5(+)/Dclk1(+)/Sox9(+) cells. Elp3 deficiency dramatically delayed tumor appearance in Apc-mutated intestinal epithelia and greatly prolonged mice survival without affecting the normal epithelium. Specific ablation of Elp3 in Lgr5(+) cells resulted in marked reduction of polyp formation upon Apc inactivation, in part due to a decreased number of Lgr5(+)/Dclk1(+)/Sox9(+) cells. Mechanistically, Elp3 is induced by Wnt signaling and promotes Sox9 translation, which is needed to maintain the subpool of Lgr5(+)/Dclk1(+) cancer stem cells. Consequently, Elp3 or Sox9 depletion led to similar defects in Dclk1(+) cancer stem cells in ex vivo organoids. Finally, Elp3 deficiency strongly impaired radiation-induced intestinal regeneration, in part because of decreased Sox9 protein levels. Together, our data demonstrate the crucial role of Elp3 in maintaining a subpopulation of Lgr5-derived and Sox9-expressing cells needed to trigger Wnt-driven tumor initiation in the intestine.
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    • "A novel cell type (termed tuft cells) was recently found to exist within the small intestinal epithelium (Gerbe, et al., 2011). Tuft cells appear to occur in both the small and large intestine and have a unique morphology and may have roles in both chemosensation, local inflammatory mediation and other possibly other secretory processes (Gerbe, Legraverend, & Jay, 2012; Nakanishi, Seno, Fukuoka, Ueo, Yamaga, Maruno, et al., 2012). "
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    • "This finding strongly suggests that HCcB accumulated in a subset of intestinal cells devoid of apical brush border, and raises the question whether BoNT/B uses specific cells for its transport through the intestinal barrier? To address this question, we investigated whether the HCcB labeled cells belong to a specific sub-population of the intestinal epithelium, using various markers of already characterized cell subsets of the intestinal epithelium: wheat germ agglutinin (WGA) which binds specifically to sialic acid and N-acetylglucosaminyl carbohydrate residues in mucous of goblet cells (Jang et al., 2004), Lectin Urex europeus agglutinin type 1 (UEA1) which recognizes Paneth cells (Garabedian et al., 1997), antibodies anti-CD3 and anti-CD11C two markers of lymphocytes and dendritic cells, respectively, which are localized in the intestinal lamina propria (Montufar-Solis et al., 2007, Persson et al., 2013), anti-villous M cells shown to be the principal site of gut luminal antigen uptake (Jang et al., 2004), chromogranin A which represents a common marker of enteroendocrine cells (Portela-Gomes et al., 2000), and the double cortin kinase 1 protein (DCLK1) specific of tuft cells, a class of secretory intestinal cells distinct from enteroendocrine cells, Paneth, cells and goblet cells (Gerbe et al., 2011). Additional markers This article is protected by copyright. "
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