第二十三型絲胺酸蛋白酶於心臟發育之研究｜國立清華大學博碩士論文庫

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研究生：	陳怡卉
論文名稱：	第二十三型絲胺酸蛋白酶於心臟發育之研究 Investigation on the role of PRSS23 in Heart Development
指導教授：	莊永仁
口試委員:	吳華林葉宏一黃聲蘋王學孝莊永仁
學位類別：	博士 Doctor
系所名稱：	生命科學暨醫學院 - 生物資訊與結構生物研究所 Institute of Bioinformatics and Structural Biology
論文出版年：	2013
畢業學年度：	101
語文別：	英文
論文頁數：	107
中文關鍵詞：	第二十三型絲胺酸蛋白酶、Snail 、內皮至間葉細胞形態的轉化、心臟瓣膜發育、心室心房結構發育、斑馬魚
外文關鍵詞：	PRSS23, Snail, EndoMT, Cardiac valve formation, Cardiac looping, Zebrafish
相關次數：	點閱：4 下載：0
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在胚胎心臟發育的過程中，心臟腔室的發育是極為重要的過程，其包含了心室心房結構的發育(cardiac looping)及心臟瓣膜的發育(cardiac valve formation)，在這過程中，各種的酵素參與其中，然而此調控機制複雜且多變，有許多細節尚待釐清；第二十三型絲胺酸蛋白酶(PRSS23)為表現在血管內皮細胞中的新穎絲胺酸蛋白酶，在先前的研究指出，第二十三型絲胺酸蛋白酶會大量表現在小鼠心臟發育時期的心室、心房以及心臟瓣膜，但其功能卻不明瞭。本篇論文主要在了解在心臟發育過程中第二十三型絲胺酸蛋白酶所扮演的腳色為何。
我們利用分別在血管及心臟會表現綠色螢光蛋白的轉殖基因魚作為研究的動物模式系統。首先，我們取得與人類第二十三型絲胺酸蛋白酶同源的斑馬魚第二十三型絲胺酸蛋白酶基因；然後利用全覆式原位雜交(whole-mount in situ hybridization)觀察到在斑馬魚胚胎發育過程中，第二十三型絲胺酸蛋白酶會表現在心室、心房與心室心房交接的瓣膜發育位置；利用反義寡核甘酸(morpholino oligonucleotide)抑制第二十三型絲胺酸蛋白酶的蛋白質表現後，發現其會導致斑馬魚心室心房發育結構與心臟瓣膜發育異常；有趣的事，將第二十三型絲胺酸蛋白酶被預測出有蛋白脢水解功能的胺基酸突變後，在與反義寡核甘酸一起打入後，突變後的第二十三型絲胺酸蛋白酶可以有效的恢復因抑制第二十三型絲胺酸蛋白酶的蛋白質表現所導致的心室心房發育結構不正常，卻不能恢復心臟瓣膜發育異常，這結果暗示了第二十三型絲胺酸蛋白酶在心臟腔室與心臟瓣膜發育所扮演的角色可能是不同的；經由測量細胞增生狀況(BrdU incorporation assay), 抑制第二十三型絲胺酸蛋白酶的蛋白質表現會影響心肌細胞的生長造成心室心房發育結構不正常；在而組織螢光染色(immunohistochemistry)的結果顯示出在第二十三型絲胺酸蛋白酶表現量受抑制時，位於瓣膜發育處的內皮層細胞進行內皮至間葉細胞形態的轉化(Endothelial to mesenchymal transition)被抑制。為了更進一步研究第二十三型絲胺酸蛋白酶所參與內皮至間葉細胞形態的轉化中的分子機制，我們利用短夾干擾型核醣核酸(shRNA)在人類主動脈內皮層細胞上抑制第二十三型絲胺酸蛋白酶以進行細胞層次的研究；結果指出，抑制第二十三型絲胺酸蛋白酶的表現除了會使得人類動脈內皮層細胞停滯進行乙型轉化生長因子(Transforming growth factor β)所誘發的細胞形態轉化，也會抑制轉錄因子Snail的活性。另一項研究顯示，大量表現人類的第二十三型絲胺酸蛋白酶與Snail在斑馬魚中，可以有效恢復因抑制第二十三型絲胺酸蛋白酶所導致的心臟瓣膜發育異常，且大量表現人類的第二十三型絲胺酸蛋白酶，也可以恢復因抑制第二十三型絲胺酸蛋白酶蛋白質表象而導致表現量降低的Snail表現量。細胞與斑馬魚的實驗結果，證明了在內皮至間葉細胞形態的轉化中，第二十三型絲胺酸蛋白酶位於Snail上游，也證實第二十三型絲胺酸蛋白酶在心臟瓣膜發育功能在演化上是高度被包留。
本篇研究是第一篇指出第二十三型絲胺酸蛋白酶與Snail上下游關係在心臟瓣膜發育時，內皮至間葉細胞形態的轉化中不可或缺的因子，並且第二十三型絲胺酸蛋白酶的功能在演化上也是高度被保留的；除此之外，在心室、心房發育過程中，本篇也指出第二十三型絲胺酸蛋白酶也會影響心肌細胞的再生。

Cardiac chamber formation, including cardiac looping and valve formation, is a vital process involving the action of protease during embryonic heart development. Nevertheless, the regulation of these proteases during cardiac chamber formation is poorly understood. Previously, a novel vascular protease, PRSS23, is shown to be highly expressed at the heart during murine cardiac development. However, its functional role in vivo remains unclear to date. We thus aim to characterize the functional role of PRSS23 during cardiac development in this study.
To investigate the functional role of PRSS23 in cardiogenesis, we used a transgenic zebrafish line with fluorescent labeled vasculatures as the research system. Expression of prss23 was detected in the ventricle, atrium and atrioventricular (AV) canal during zebrafish embryonic development. We found morpholino knockdown of Prss23 caused severe cardiac defects as the developing heart failed to undergo loop formation, accompanied by the malformation of the atrioventricular canal. When zPrss23 DNA with mutative catalytic triad was co-injected with morpholino, the cardiac looping phenotype was rescued, but the valve formation was not. This data implied the malformation of AV canal was not caused by cardiac looping. Then we found morpholino knockdown of Prss23 repressed the cardiomyocyte proliferation during cardiac looping and inhibited the endothelial to mesenchymal transition (EndoMT) at the AV canal during the cardiac valve formation. Moreover, in human aortic endothelial cell-based assays, PRSS23 knockdown by shRNA not only repressed the TGF-β-induced EndoMT but also reduced Snail transcription suggesting Snail signaling is downstream of PRSS23 during EndoMT. We further demonstrated that human PRSS23 and SNAIL could rescue the prss23 morpholino-induced AV canal defect in zebrafish embryos, indicating PRSS23’s function in valvulogenesis is evolutionarily conserved.
We demonstrated for the first time that the initiation of EndoMT in valvulogenesis depends on PRSS23-Snail signaling, and the functional role of PRSS23 during AV valve formation is evolutionar

Contents
Abstract    I
中文摘要    III
誌謝辭    V
Contents    VII
Abbreviations    XIII
Chemicals and Reagents    XIII
Specialized terms    XV
Chapter 1 Introduction    1
1.1    Introduction of heart development    2
1.2    The mechanism of the cardiac looping    2
1.3    The mechanism of the valve formation    3
1.4    Protease is necessary for heart development    5
1.5    Introduction of heart development in zebrafish    6
1.6    Introduction of PRSS23    8
1.7    Specific aim    9
Chapter 2 Materials and methods    11
2.1    Zebrafish lines    12
2.2    Identification and cloning of zebrafish PRSS23    12
2.3    Phylogenetic analysis    12
2.4    Morpholino injection and DNA rescued    13
2.5    Whole-mount in situ hybridization (ISH)    15
2.6    Real-time quantitative polymerase chain reaction (RT-qPCR) and Semi- quantitative polymerase chain reaction (Semi-qPCR)    16
2.7    Immunohistochemistry (IHC)    17
2.8    Bromodeoxyuridine (BrdU) incorporation assay    18
2.9    Cell culture and TGF-β2 induced EndoMT assay    20
2.10    RNAi interferon    21
2.11    Immunocytochemistry (ICC)    22
2.12    Enzyme-linked immunosorbent assay (ELISA)    24
2.13    Image processing and Statistical analysis    24
Chapter 3 Results    26
3.1    Cloning and characterization of Prss23 in zebrafish    27
3.2    Cardiac expression of prss23 in zebrafish    27
3.3    Zebrafish Prss23 mRNA is successfully targeted using Morpholino technology    28
3.4    Prss23 function in zebrafish is essential for heart development    29
3.5    The protease function of Prss23 is necessary for the valvulogenesis, but not for the cardiac looping.    31
3.6    Prss23 knockdown decreases the cardiomyocyte proliferation to cause the defect of the cardiac looping.    32
3.7    PRSS23 is required for EndoMT initiation during cardiac valve formation.    34
3.8    Human PRSS23 expression is successfully reduced by shRNA interference.    37
3.9    Knockdown of PRSS23 suppresses TGF-β2-induced EndoMT in human aortic endothelial cells.    38
3.10    PRSS23 is required for Snail transcription under TGF-β2 stimulation.    39
3.11    Human Snail could rescue the AV canal defects caused by prss23 knockdown in zebrafish.    40
Chapter 4 Discussion and Summary    43
4.1    Significance of this study    44
4.2    PRSS23 is required for cardiac chamber formation    44
4.3    PRSS23 is essential for the TGF-β induced EndoMT    47
4.4    PRSS23 might interact TCF12 to regular Snail transcription    49
4.5    PRSS23 might play a possible role in chromosome modification and  remodeling during heart development    51
4.6    Summary    52
Bibliographies    54
Table 1. The primer list of in situ hybridization.    67
Table 2. The primer list of RT-qPCR.    68
Table 3. The primer list of Semi-PCR.    69
Table 4. The primer list of cloning.    70
Table 5. AV canal malformation phenotype frequencies in embryos at 72 h.p.f.    71
Figure    72
Figure 1. Zebrafish Prss23 is conserved among vertebrates.    72
Figure 2. Prss23 transcripts are detected in the zebrafish heart development.    74
Figure 3. Morpholino knockdown of Prss23 in zebrafish embryos.    75
Figure 4. Zebrafish Prss23 is required for cardiac looping and valve formation in AV canal during embryonic development.    77
Figure 5. Zebrafish Prss23 knockdown could not affect vasculogenesis and angiogenesis proceeds.    79
Figure 6. The enzyme function of Prss23 is involved in the cardiac valve formation, but not in the cardiac looping.    80
Figure 7. Prss23 knockdown inhibits the cardiomyocyte proliferation to caused the failure of the cardiac looping.    81
Figure 8. Prss23 knockdown disturbed the expression pattern of bmp4 and notch1b.    83
Figure 9. Prss23 knockdown inhibited EndoMT initiation during atrioventricular valve formation.    85
Figure 10. Knockdown of Prss23 reduced endocardium proliferation during valvulogenesis.    86
Figure 11. PRSS23 expression is down-regulated in HAECs by shRNA interference.    87
Figure 12. Loss of PRSS23 repressed the TGF-β2-induced EndoMT in HAECs.    88
Figure 13. PRSS23 knockdown would inhibit SNAIL transcription but not SMAD2 phosphorylation in HAECs after TGF-β2 stimulation.    90
Figure 14. PRSS23 knockdown did not affect the pSMAD2 locating into nuclei after TGF-β2 treatment.    92
Figure 15. TGF-β2 quickly induces the PRSS23 mRNA expression level in HAECs.    93
Figure 16. Human PRSS23 and Snail can rescue the prss23 morpholino-induced AV endocardiac malformation in zebrafish.    94
Figure 17. Zebrafish notch1 overexpression resulted in the death or deformity in zebrafish embryos.    96
Figure 18. A schematic diagram showing PRSS23’s function in the initiation of EndoMT during cardiac valve formation.    97
Appendix Tables    98
Table A1. The protein-protein interaction list of PRSS23.    98
Appendix figures    99
Figure A1. mRNA and Domain organization map of human PRSS23.    99
Figure A2. Enzyme Activity Curves of GST-PRSS23-P and tPA Substrate.    101
Figure A3. Endogenous PRSS23 in nucleus of MCF-7 cells.    102
Figure A4. Mutation of 257KRK259 reduces nuclear transportation in HEK293T cells.    103
Figure A5. PRSS23 mRNA expresses in ventricle and atrium during mouse cardiac development.    104
Figure A6. Human PRSS23 was highly expresses in heart and endothelial cells.    105
Figure A7. PRSS23 interact with TCF12 in HAECs.    106
Figure A8. TCF12 DNA binding site, E-box, is found in the conserved region of Snail promoter in various vertebrates.    107

                                

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