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

ABSTRACT 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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Available from: Johan H van Es, Sep 28, 2015
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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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    ABSTRACT: Botulinum neurotoxins (BoNTs) are responsible for severe flaccid paralysis (botulism) which in most cases enter the organism via the digestive tract and then disseminate into the blood or lymph circulation to target autonomic and motor nerve endings. The passage way of BoNTs alone or in complex forms with associated non-toxic proteins through the epithelial barrier of the digestive tract still remains unclear. Here we show using an in vivo model of mouse ligated intestinal loop that BoNT/B alone or the BoNT/B C-terminal domain of the heavy chain (HCcB), which interacts with cell surface receptors, translocate across the intestinal barrier. The BoNT/B or HCcB translocation through the intestinal barrier occurred via an endocytosis-dependent mechanism within 10-20 min, since Dynasore, a potent endocytosis inhibitor, significantly prevented BoNT/B as well as HCcB translocation. We also show that HCcB or BoNT/B specifically target neuronal cells and neuronal extensions in the intestinal submucosa and musculosa expressing synaptotagmin, preferentially cholinergic neurons and to a lower extent other neuronal cell types, notably serotoninergic neurons. Interestingly, rare intestinal epithelial cells accumulated HCcB suggesting that distinct cell types of the intestinal epithelium, still undefined, might mediate efficient translocation of BoNT/B. This article is protected by copyright. All rights reserved.
    Cellular Microbiology 08/2015; DOI:10.1111/cmi.12502 · 4.92 Impact Factor
    • "Anothertypeofendocrinecell,theTuftcell,comprises0.4%oftheintestinalepithelium(Gerbeet al.2012)andhasgarneredmuchattentionoverthepastfiveyearsduetothediscoveryoftheirdistinct celllineage.Althoughtheyrequirethepan-endocrinetranscriptionfactorAtoh1fordifferentiation,Tuft cellsdonotrequiretheotherfactorsnecessaryforenteroendocrine,goblet,orPanethcellspecification (Gerbeetal.2011).TuftcellsaremarkedbyexpressionofDclk1,andhavebeenshowntocontributeto intestinalrecoveryfollowinginjury(Gerbeetal.2009;Westphalenetal.2014).Dclk1isalsoaputative cancerstemcellmarker,andlossofDclk1+cellsabrogatestumorigenesisontheApcMin/+colorectal cancermousemodel(Nakanishietal.2013;Mayetal.2008). "
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    ABSTRACT: The intestinal epithelium is an ideal model system for the study of normal and pathological differentiation processes. The mammalian intestinal epithelium is a single cell layer comprising proliferative crypts and differentiated villi. The crypts contain both proliferating and quiescent stem cell populations that self-renew and produce all the differentiated cell types, which are replaced every 3-5 days. The genetics of intestinal development, homeostasis, and disease are well defined, but less is known about the contribution of epigenetics in modulating these processes. Epigenetics refers to heritable phenotypic traits, including gene expression, which are independent of mutations in the DNA sequence. We have known for several decades that human colorectal cancers contain hypomethylated DNA, but the causes and consequences of this phenomenon are not fully understood. In contrast, tumor suppressor gene promoters are often hypermethylated in colorectal cancer, resulting in decreased expression of the associated gene. In this review, we describe the role that epigenetics plays in intestinal homeostasis and disease, with an emphasis on results from mouse models. We highlight the importance of producing and analyzing next-generation sequencing data detailing the epigenome from intestinal stem cell to differentiated intestinal villus cell.
    Cellular and Molecular Life Sciences CMLS 07/2015; DOI:10.1007/s00018-015-1997-9 · 5.81 Impact Factor
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    • "COX-2 is expressed in tumor epithelial cells and their surrounding stromal cells, while DCAMKL1 is expressed in epithelial cells, but not in their surrounding stromal cells. DCAMKL1 is a cell surface expression protein, and a specific antibody against the extracellular domain of DCAMKL1 has been used for immunohistochemistry in mice.2 However, an adequate antibody for DCAMKL1 for immunohistochemistry for human tissue is currently unavailable. "
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    ABSTRACT: Background/Aims Doublecortin and CaM kinase-like-1 (DCAMKL1) is a marker of stem cells expressed predominantly in the crypt base in the intestine. However, DCAMKL1-positive cells have been shown to be differentiated tuft cells rather than quiescent progenitors. Tuft cells are the only epithelial cells that express cyclooxygenase 2 (COX-2) in the normal intestinal epithelium. We previously generated Cdx2-transgenic mice as model mice for intestinal metaplasia and gastric carcinoma. In the current study, we investigated the association between COX-2 and DCAMKL1 in gastric carcinoma. Methods We examined the association between COX-2 and DCAMKL1 expression in gastric carcinomas in clinical samples (early gastric well-differentiated adenocarcinoma) and Cdx2-transgenic mice; and the DCAMKL1-transgenic mouse stomach using immunohistochemistry and quantitative real-time polymerase chain reaction. Results The COX-2-expressing cells were scattered, not diffusely expressed, in gastric carcinomas from humans and Cdx2-transgenic mice. DCAMKL1-positive cells were also scattered in the gastric carcinomas, indicating that tuft cells could still be present in gastric carcinoma. COX-2 was expressed in DCAMKL1-positive tuft cells in Cdx2- and DCAMKL1-transgenic mouse stomachs, whereas the Sox9 transcription factor was ubiquitously expressed in gastric carcinomas, including COX-2-positive cells. Conclusions COX-2 is expressed in DCAMKL1-expressing quiescent tuft cells in gastric carcinoma.
    Gut and liver 09/2014; 8(5):508-18. DOI:10.5009/gnl13237 · 1.81 Impact Factor
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