The Zinc Finger Transcription Factor PLAGL2 Enhances Stem Cell Fate and Activates Expression of ASCL2 in Intestinal Epithelial Cells

AbstractTranscription factor Neurod1 is required for enteroendocrine progenitor differentiation and maturation. Several earlier studies indicated that ectopic expression of Neurod1 converted non- neuronal cells into neurons. However, the functional consequence of ectopic Neurod1 expression has not been examined in the GI tract, and it is not known whether Neurod1 can similarly switch cell fates in the intestine. We generated a mouse line that would enable us to conditionally express Neurod1 in intestinal epithelial cells at different stages of differentiation. Forced expression of Neurod1 throughout intestinal epithelium increased the number of EECs as well as the expression of EE specific transcription factors and hormones. Furthermore, we observed a substantial reduction of Paneth cell marker expression, although the expressions of enterocyte-, tuft- and goblet-cell specific markers are largely not affected. Our earlier study indicated that Neurog3+ progenitor cells give rise to not only EECs but also Goblet and Paneth cells. Here we show that the conditional expression of Neurod1 restricts Neurog3+ progenitors to adopt Paneth cell fate, and promotes more pronounced EE cell differentiation, while such effects are not seen in more differentiated Neurod1+ cells. Together, our data suggest that forced expression of Neurod1 programs intestinal epithelial cells more towards an EE cell fate at the expense of the Paneth cell lineage and the effect ceases as cells mature to EE cells.

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Activation of NF-κB in intestinal epithelial cells by enteropathogenicEscherichia coli

AJP Cell Physiology ◽

10.1152/ajpcell.1997.273.4.c1160 ◽

1997 ◽

Vol 273 (4) ◽

pp. C1160-C1167 ◽

Cited By ~ 198

Author(s):

Suzana D. Savkovic ◽

Athanasia Koutsouris ◽

Gail Hecht

Keyword(s):

Transcription Factor ◽

Epithelial Cells ◽

Intestinal Epithelial Cells ◽

Bacterial Flora ◽

Inflammatory Cells ◽

Initial Response ◽

Intestinal Epithelial ◽

E Coli ◽

Normal Bacterial Flora ◽

First Time

The initial response to infection is recruitment of acute inflammatory cells to the involved site. Interleukin (IL)-8 is the prototypical effector molecule for this process. Transcription of the IL-8 gene is primarily governed by the nuclear transcription factor (NF)-κB. Intestinal epithelial cells produce IL-8 in response to infection by enteric pathogens yet remain quiescent in a milieu where they are literally bathed in normal bacterial flora. We therefore sought to investigate NF-κB activation in response to enteropathogenic Escherichia coli (EPEC), nonpathogenic E. coli, and bacterial lipopolysaccharide in an intestinal epithelial cell (T84) model and to determine whether EPEC-induced activation of NF-κB factor is causally linked to IL-8 production. We report herein that NF-κB is activated by EPEC, yet such a response is not extended to nonpathogenic organisms or purified E. coli lipopolysaccharide. Transcription factor decoys significantly diminished IL-8 production in response to EPEC, demonstrating a causal relationship. Furthermore, deletion of specific EPEC virulence genes abrogates the NF-κB-activating property of this pathogen, suggesting that specific bacterial factors are crucial for inducing this response. These studies show for the first time that infection of intestinal epithelial cells with EPEC activates NF-κB, which in turn initiates IL-8 transcription, and highlight the differential response of these cells to bacterial pathogens vs. nonpathogens.

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Stem Cell Fate Specification: Role of Master Regulatory Switch Transcription Factor PU.1 in Differential Hematopoiesis

Stem Cells and Development ◽

10.1089/scd.2005.14.140 ◽

2005 ◽

Vol 14 (2) ◽

pp. 140-152 ◽

Cited By ~ 31

Author(s):

Gurudutta U. Gangenahalli ◽

Pallavi Gupta ◽

Daman Saluja ◽

Yogesh K. Verma ◽

Vimal Kishore ◽

...

Keyword(s):

Transcription Factor ◽

Stem Cell ◽

Cell Fate ◽

Cell Fate Specification ◽

Stem Cell Fate ◽

Fate Specification

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Hyperthermia-induced heat shock activates the transcription factor C/EBP-β and augments IL-6 production in human intestinal epithelial cells

Journal of the American College of Surgeons ◽

10.1016/s1072-7515(02)01342-x ◽

2002 ◽

Vol 195 (5) ◽

pp. 619-626 ◽

Cited By ~ 8

Author(s):

Eric S Hungness ◽

Bruce W Robb ◽

Guang-ju Luo ◽

Dan D Hershko ◽

Per-Olof Hasselgren

Keyword(s):

Transcription Factor ◽

Heat Shock ◽

Epithelial Cells ◽

Intestinal Epithelial Cells ◽

Intestinal Epithelial ◽

Human Intestinal Epithelial Cells ◽

Factor C

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Amelioration of Congenital Tufting Enteropathy in EpCAM (TROP1)-Deficient Mice via Heterotopic Expression of TROP2 in Intestinal Epithelial Cells

Cells ◽

10.3390/cells9081847 ◽

2020 ◽

Vol 9 (8) ◽

pp. 1847

Author(s):

Gaku Nakato ◽

Sohshi Morimura ◽

Michael Lu ◽

Xu Feng ◽

Chuanjin Wu ◽

...

Keyword(s):

Stem Cell ◽

Epithelial Cells ◽

Cell Function ◽

Intestinal Epithelial Cells ◽

Surface Proteins ◽

Stem Cell Markers ◽

Intestinal Epithelial ◽

Mesenteric Lymph Nodes ◽

Function Expression ◽

Deficient Mice

TROP1 (EpCAM) and TROP2 are homologous cell surface proteins that are widely expressed, and often co-expressed, in developing and adult epithelia. Various functions have been ascribed to EpCAM and TROP2, but responsible mechanisms are incompletely characterized and functional equivalence has not been examined. Adult intestinal epithelial cells (IEC) express high levels of EpCAM, while TROP2 is not expressed. EpCAM deficiency causes congenital tufting enteropathy (CTE) in humans and a corresponding lethal condition in mice. We expressed TROP2 and EpCAM in the IEC of EpCAM-deficient mice utilizing a villin promoter to assess EpCAM and TROP2 function. Expression of EpCAM or TROP2 in the IEC of EpCAM knockout mice prevented CTE. TROP2 rescue (T2R) mice were smaller than controls, while EpCAM rescue (EpR) mice were not. Abnormalities were observed in the diameters and histology of T2R small intestine, and Paneth and stem cell markers were decreased. T2R mice also exhibited enlarged mesenteric lymph nodes, enhanced permeability to 4 kDa FITC-dextran and increased sensitivity to detergent-induced colitis, consistent with compromised barrier function. Studies of IEC organoids and spheroids revealed that stem cell function was also compromised in T2R mice. We conclude that EpCAM and TROP2 exhibit functional redundancy, but they are not equivalent.

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