Mammalian anterior gradient 2 (AGR2), an endoplasmic reticulum (ER) protein disulfide-isomerase (PDI), is involved in cancer cell growth and metastasis, asthma and inflammatory bowel disease (IBD). Mice lacking Agr2 exhibit decreased Muc2 protein in intestinal goblet cells, abnormal Paneth cell development, ileitis and colitis. Despite its importance in cancer biology and inflammatory diseases, the mechanisms regulating agr2 expression in the gastrointestinal tract remain unclear. In the present study, we investigated the mechanisms that control agr2 expression in the pharynx and intestine of zebrafish by transient/stable transgenesis, coupled with motif mutation, morpholino knockdown, mRNA rescue and ChIP. A 350 bp DNA sequence with a hypoxia-inducible response element (HRE) and forkhead-response element (FHRE) within a region −4.5 to −4.2 kbp upstream of agr2 directed EGFP expression specifically in the pharynx and intestine. No EGFP expression was detected in the intestinal goblet cells of Tg(HREM:EGFP) or Tg(FHREM:EGFP) embryos with mutated HRE or FHRE, whereas EGFP was expressed in the pharynx of Tg(HREM:EGFP), but not Tg(FHREM:EGFP), embryos. Morpholino knockdown of foxa1 (forkhead box A1) reduced agr2 levels in the pharynx, whereas knockdown of foxa2 or hif1ab decreased intestinal agr2 expression and affected the differentiation and maturation of intestinal goblet cells. These results demonstrate that Foxa1 regulates agr2 expression in the pharynx, whereas both Foxa2 and Hif1ab control agr2 expression in intestinal goblet cells to regulate maturation of these cells.
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Research Article|
July 12 2016
Foxa2 and Hif1ab regulate maturation of intestinal goblet cells by modulating agr2 expression in zebrafish embryos
Yun-Ren Lai;
Yun-Ren Lai
*Department of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung 202, Taiwan, R.O.C.
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Yu-Fen Lu;
Yu-Fen Lu
†Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 115, Taiwan, R.O.C.
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Huang-Wei Lien;
Huang-Wei Lien
‡Institute of Biological Chemistry, Academia Sinica, Nankang, Taipei 115, Taiwan, R.O.C.
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Chang-Jen Huang;
Chang-Jen Huang
‡Institute of Biological Chemistry, Academia Sinica, Nankang, Taipei 115, Taiwan, R.O.C.
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Sheng-Ping L. Hwang
Sheng-Ping L. Hwang
1
*Department of Bioscience and Biotechnology, National Taiwan Ocean University, Keelung 202, Taiwan, R.O.C.
†Institute of Cellular and Organismic Biology, Academia Sinica, Taipei 115, Taiwan, R.O.C.
1To whom correspondence should be addressed (email zoslh@gate.sinica.edu.tw).
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Publisher: Portland Press Ltd
Received:
April 21 2016
Revision Received:
May 23 2016
Accepted:
May 24 2016
Accepted Manuscript online:
May 24 2016
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society
2016
Biochem J (2016) 473 (14): 2205–2218.
Article history
Received:
April 21 2016
Revision Received:
May 23 2016
Accepted:
May 24 2016
Accepted Manuscript online:
May 24 2016
Citation
Yun-Ren Lai, Yu-Fen Lu, Huang-Wei Lien, Chang-Jen Huang, Sheng-Ping L. Hwang; Foxa2 and Hif1ab regulate maturation of intestinal goblet cells by modulating agr2 expression in zebrafish embryos. Biochem J 15 July 2016; 473 (14): 2205–2218. doi: https://doi.org/10.1042/BCJ20160392
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