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研究生:賴韻仁
研究生(外文):Lai, Yun-Ren
論文名稱:Foxa2和Hif1ab調控agr2表現進而影響斑馬魚腸道杯狀細胞成熟之研究
論文名稱(外文):Foxa2 and Hif1ab regulate maturation of intestinal goblet cells by modulating agr2 expression in zebrafish embryos
指導教授:黃聲蘋
指導教授(外文):Hwang, Sheng-Ping
口試委員:黃銓珍胡清華喻秋華江運金
口試委員(外文):Huang, Chang-JenHu, Chin-HwaYuh, Chiou-JwaJiang, Yun-Jin
口試日期:2016-07-11
學位類別:博士
校院名稱:國立臺灣海洋大學
系所名稱:生命科學暨生物科技學系
學門:生命科學學門
學類:生物科技學類
論文種類:學術論文
論文出版年:2016
畢業學年度:104
語文別:英文
論文頁數:106
中文關鍵詞:斑馬魚腸道杯狀細胞咽喉agr2foxa1foxa2hif1ab
外文關鍵詞:zebrafishintestinal goblet cellpharynxagr2foxa1foxa2hif1ab
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在過去的研究當中已知,anterior gradient 2 (AGR2) 是一種位於內質網的雙硫鍵異構酶,涉及癌細胞的增生與轉移、氣喘和發炎性腸炎,agr2基因剃除鼠腸道聚有以下現象:杯狀細胞的Muc2蛋白表現量下降、潘氏細胞發育異常、產生腸炎等。本實驗室先前發現,agr2會調控腸道杯狀細胞末期分化。儘管目前已知agr2在癌症生物學與發炎相關疾病扮演重要角色,但agr2在腸道表現的調控機制目前尚未釐清。本論文利用短暫及穩定表達agr2啟動子的轉殖基因斑馬魚,配合突變結合位點及morphorlino下調其表現,mRNA救援及染色質免疫沉澱法來研究其機制。我發現介於-4.5k到-4.2k的350bp 具有專一調控綠螢光表現於咽喉與腸道杯狀細胞的能力,進一步分別突變hypoxia-inducible response element (HRE) 和 fork head response element (FHRE)的結合序列,發現在Tg(HREM:EGFP)的胚胎中,綠螢光無法表現在腸道杯狀細胞,而Tg(FHREM: EGFP)胚胎中,綠螢光也無法表現在咽喉與腸道杯狀細胞。在斑馬魚中,foxa家族的foxa1、foxa2和foxa3皆表現在咽喉與腸道;hif 家族中,hif1ab與epas1b (又名hif2α) 表現於腸道。進一步利用MO,分別將foxa1、foxa2與hif1ab短暫剔除,發現在胚胎受精後58小時的時候,Foxa1影響agr2 mRNA在咽喉的表現,在胚胎受精後102小時的時候,Foxa2與Hif1ab控制agr2 mRNA表現在腸道杯狀細胞同時影響腸道杯狀細胞的增生與成熟。利用染色質免疫沉澱技術(ChIP)證明Foxa1,Foxa2與Hif1ab三個轉錄因子皆直接結合agr2啟動子序列。本實驗證明Foxa1直接調控agr2在咽喉的表現,Foxa2與Hif1ab直接控制agr2在腸道杯狀細胞的表現,進而調控腸道杯狀細胞的成熟。此外,也證明Hif1ab-Agr2路徑參與TNBS誘發斑馬魚腸道發炎動物模式。
Mammalian anterior gradient 2 (AGR2), an endoplasmic reticulum protein disulfide isomerase, is involved in cancer cell growth and metastasis, asthma, and inflammatory bowel disease. Mice lacking Agr2 exhibit decreased Muc2 protein in intestinal goblet cells, abnormal Paneth cell development, ileitis, and colitis. Previous study from our lab had found AGR2 regulates the differentiation of intestinal goblet cells. Despite its importance in cancer biology and inflammatory diseases, the mechanisms regulating agr2 expression in the gastrointestinal tract remain unclear. Here, 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 chromatin immunoprecipitation. A 350 bp DNA sequence with a hypoxia-inducible response element (HRE) and fork head 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, while EGFP was expressed in the pharynx of Tg(HREM:EGFP), but not Tg(FHREM:EGFP), embryos. In zebrafish foxa family (foxa1, foxa2 and foxa3) all expressed in the pharynx and intestine, hif1ab and epas1b expressed in the intestine. Morpholino knockdown of foxa1 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. Using chromatin immunoprecipitation, we proved that Foxa1, Foxa2 and Hif1ab can bind to the promoter region of agr2. These results demonstrate that Foxa1 regulates agr2 expression in the pharynx, while both Foxa2 and Hif1ab control agr2 expression in intestinal goblet cells to regulate maturation of these cells. Furthermore, we show that the Hif1ab-Agr2 pathway is involved in a zebrafish model of TNBS-induced enterocolitis.
誌謝 ........................................................................................................................ i
Abstract (Chinese) ................................................................................................. ii
Abstract (English) .................................................................................................. iii
Contents .................................................................................................................. iv
1. Introduction ........................................................................................................ 1
1.1 Agr2 ............................................................................................................... 1
1.2 Inflammatory bowel disease ........................................................................ 7
1.3 Hypoxia-inducible factor ............................................................................. 15
1.4 Foxa ............................................................................................................... 17
1.5 Zebrafish intestinal development ............................................................... 20
2. Experimental methods ....................................................................................... 27
2.1 Zebrafish strains and maintenance ............................................................ 27
2.2 Plasmid construction ................................................................................... 27
2.3 Generation of germline transgenic zebrafish ............................................ 32
2.4 Morpholino and mRNA injection ............................................................... 32
2.5 Whole-mount in situ hybridization, double fluorescence in situ
hybridization, and signal intensity quantification .................................... 33
2.6 Whole Mount Wheat Germ Agglutinin (WGA) staining ......................... 35
2.7 Alcian blue staining and quantification of goblet cell number and area 35
2.8 TNBS treatment ............................................................................................ 36
2.9 Photography .................................................................................................. 36
2.10 Chromatin Immunoprecipitation (ChIP) and ChIP-quantitative PCR 36
3. Results ................................................................................................................. 39
3.1 A 350 bp DNA sequence within the -4.5 to -4.2 kbp region upstream
of agr2 confers specific EGFP expression in the gastrointestinal tract
of zebrafish embryos ....................................................................................... 39
3.2 Intact hypoxia-response and fork head response elements are
required for EGFP expression in the gastrointestinal tract of
zebrafish embryos ........................................................................................ 41
3.3 Hif1ab regulates intestinal agr2 expression and modulates the
differentiation and maturation of intestinal goblet cells .......................... 43
3.4 Foxa2 modulates intestinal agr2 expression and regulates the
differentiation and maturation of intestinal goblet cells while
Foxa1 regulates agr2 expression in the pharynx ....................................... 47
3.5 Hif1ab and Foxa2 function synergistically in the regulation of
agr2 expression and the differentiation and maturation of
intestinal goblet cells .................................................................................... 50
3.6 Foxa1, Foxa2, and Hif1ab directly bind to FHRE or HRE motifs
located upstream of agr2 ............................................................................. 51
3.7 Increased goblet cell number and Agr2 expression in the
intestines of TNBS-treated embryos may be dependent on hif1ab
expression ...................................................................................................... 52
4. Discussion ............................................................................................................ 54
5. Conclusion ........................................................................................................... 63
6. Reference ............................................................................................................. 66
7. Figure ................................................................................................................... 77
Figure 1. EGFP expression in embryos (F0) injected with the indicated
constructs containing various lengths of the 5′-upstream
region of agr2,and in the F1 generation ............................................ 78
Figure 2. EGFP-positive cells are located in Wheat Germ Agglutinin
-stained goblet cells in the pharynx and intestine ............................ 79
Figure 3. EGFP is co-expressed with shha in the pharynx ............................. 80
Figure 4. HRE and FHRE motifs within the -4.5 to -4.2 kbp region
upstream of agr2 are required for directing EGFP
expression in the intestinal goblet cells, pharynx, and/or
skin mucous cells ................................................................................ 81
Figure 5. Expression patterns of hif1aa, hif1ab, epas1a, epas1b, hif1al,
and hif1al2 .......................................................................................... 83
Figure 6. Analyses of the specificity and efficacy of hif1ab MO and
epas1b MO .......................................................................................... 84
Figure 7. Intestinal agr2 expression and differentiation and maturation
of intestinal goblet cells are regulated by Hif1ab ............................ 85
Figure 8. Epas1b regulates the differentiation and maturation of
intestinal goblet cells, but not intestinal agr2 expression ............... 87
Figure 9. Expression patterns of foxa1, foxa2, and foxa3 .............................. 88
Figure 10. Analyses of the specificity and efficacy of foxa1 MO, foxa2
MO, and foxa3 MO .......................................................................... 89
Figure 11. Foxa2 modulates intestinal agr2 expression and the
differentiation and maturation of intestinal goblet cells .............. 90
Figure 12. Foxa1 regulates the differentiation and maturation of
intestinal goblet cells, but not intestinal agr2 expression ............. 92
Figure 13. Foxa3 regulates the differentiation and maturation of
intestinal goblet cells, but not intestinal agr2 expression ............. 93
Figure 14. Knockdown of foxa1 reduces agr2 expression in the
pharynx ............................................................................................. 94
Figure 15. Co-injection of low amounts of hif1ab and foxa2 MO has
synergistic effects on the differentiation and maturation
of intestinal goblet cells and intestinal agr2 expression ................ 95
Figure 16. Foxa1, Foxa2, and Hif1ab directly bind to FHRE or
HRE motifs located upstream of the agr2 promoter .................... 96
Figure 17. Increased goblet cell number and Agr2 expression in
the intestines of TNBS-treated embryos may be dependent
on hif1ab expression ......................................................................... 97
Figure 18. The differentiation of enteroendocrine cells in the
intestines was affected in foxa1, foxa2, and hif1ab
morphants ......................................................................................... 99
Figure 19. Enterocyte differentiation in the intestines of hif1ab,
foxa1, foxa2, foxa3 and hif1ab morphants was not
affected .............................................................................................. 100
Figure 20 Expression of muc2.1 in intestinal goblet cells is not
altered in hif1ab, epas1b, foxa1, foxa2, or foxa3
morphants ......................................................................................... 101
Figure 21 EGFP expression in embryos (F0) injected with the
indicated constructs containing HuHRE, HuHREM,
HuFHRE, HuFHREM, or HuHF motifs within
350endo-EGFP, and in the F1 generation ...................................... 102
Figure 22. Proposed model for regulatory mechanisms of
agr2 expression in the pharynx and intestinal
goblet cells ......................................................................................... 104
Figure 23. Proposed model for the involvement of Hif1ab-Agr2
pathway in TNBS-induced enterocolitis zebrafish model ............ 105
8. Appendix ............................................................................................................. 106

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