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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 林淑華(Shu-Wha Lin) | |
| dc.contributor.author | Chun-Yu Chen | en |
| dc.contributor.author | 陳軍宇 | zh_TW |
| dc.date.accessioned | 2021-06-16T23:30:06Z | - |
| dc.date.available | 2017-09-18 | |
| dc.date.copyright | 2012-09-18 | |
| dc.date.issued | 2012 | |
| dc.date.submitted | 2012-07-28 | |
| dc.identifier.citation | 1 Hershko, A. and Ciechanover, A. (1998) The ubiquitin system. Annu Rev Biochem, 67, 425-479.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/65211 | - |
| dc.description.abstract | 在真核細胞中，蛋白質的降解系統主要作用於清除受損或是不需要的蛋白來維持細胞的正常生理。蛋白質降解受到嚴密的調控，以免對細胞內正在執行正常生理功能的蛋白造成損害。泛素 (ubiquitin) 為在真核細胞物種之間具備高度同源性的小分子蛋白。當細胞需要降解特定蛋白時，會利用一組特別的酵素系統將泛素連接到目標蛋白上。一旦目標蛋白重複被接上泛素而形成泛素鏈後，26S蛋白酶體會辨認出具有泛素鍵的蛋白將其分解。泛素連接到目標蛋白上需要靠泛素連結酶 (ubiquitin ligase, E3) 在正確的時間地點將泛素連結到目標蛋白上使其被26S蛋白酶體所分解。在真核細胞中眾多的泛素連結酶中，cullin蛋白為其中最大的家族。Cullin 4b (Cul4b)是cullin 家族的成員之一，位於X染色體上。在人類中，CUL4B基因突變後會導致X染色體遺傳性智能遲緩(X-linked mental retardation)。
本論文以條件式基因剔除策略，用不同的Cre基因轉殖小鼠建立Cul4b基因剔除小鼠來研究Cul4b的生理功能。利用Prm1-Cre基因轉殖小鼠來剔除Cul4b基因時，發現Cul4b基因剔除小鼠在胚胎發育早期便會死亡，顯示Cul4b基因對於胚胎發育的重要性。當利用Sox2-Cre基因轉殖小鼠在越過胚胎發育早期的時間點(第6.5~7.5天)後才剔除Cul4b基因時，此Cul4b基因剔除小鼠能夠存活。但此小鼠在經過動物行為測試及海馬迴神經樹突複雜度的測量後證實Cul4b基因剔除小鼠有智能遲緩的特徵。研究上述兩種Cul4b基因剔除小鼠的致病機制後，可以幫助我們了解Cul4b在胚胎發育及智能遲緩中所扮演的角色。 | zh_TW |
| dc.description.abstract | In eukaryotes, the main function of protein degradation system is to degrade damaged or unneeded proteins to maintain the normal cellular physiology. Protein degradation is rigidly controlled to avoid damaging the proteins which are executing normal biological functions in cell. Ubiquitin is a small protein which is highly conserved among eukaryotic species. When specific proteins are needed to be degraded, ubiquitin will be covalently ligated to targeted protein via specific enzyme systems. Once the targeted proteins are ligated by ubiquitin repeatedly to form a poly-ubiquitin chain, 26S proteasome will recognize the targeted proteins which are labeled by poly-ubiquitin chains and then degrade them. The ligation of ubiquitin to targeted proteins and recognition of 26S proteasome in the appropriate time and space needs E3 ubiquitin ligases. Among a large amount of E3 ligases in eukaryotes, cullin proteins are the largest family. Cullin 4b (Cul4b) located on X chromosome is one of the members in cullin family. In human, mutation in CUL4B results in X-linked mental retardation.
This dissertation describes the conditional knockout strategy by using different Cre transgenic mice to study the biological function of Cul4b. Deletion of Cul4b by Protamine-1-Cre transgenic mice leading to early embryo lethal suggests that Cul4b plays an important role in mouse embryo development. When the Sox2-Cre transgenic mice are used to delete Cul4b beyond the time of early embryonic development (E6.5 to E7.5), Cul4b knockout mice are viable. Characterization of Cul4b knockout mice through behavioral test and examination of dendritic complexity demonstrate that Cul4b knockout mice represent the mental retardation syndrome. To study the pathogenic mechanism of two Cul4b knockout mice mentioned above helps us to understand the important role of Cul4b in embryonic development and mental retardation. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T23:30:06Z (GMT). No. of bitstreams: 1 ntu-101-F92424003-1.pdf: 8988065 bytes, checksum: 28c58a9fd9232aa99e94c9d0df7a2a12 (MD5) Previous issue date: 2012 | en |
| dc.description.tableofcontents | 口試委員審定書………………………………………………………………….……...i
誌謝……………………………………………………………………………….……..ii 序言……………………………………………………………………………………..iii Preface..…...…………………………………………………………………………....iv Contents…...……………………………………………………………………….......vi Abbreviation…..…………………………………………………………………….....xi List of figures……...…………………………………………………………….........xiii List of tables…………………………………………………………………………...xv List of appendix tables……………………………………………………………….xvi List of appendixes...…………………………………………………………………xvii Section 1 The Role of Cul4b in embryogenesis………………………….…………….1 摘要…….………………………………………………………………….…………….2 Abstract………………………………………………………………….……………...3 Chapter I Introduction……………………………………………………………...…5 1.1 Ubiquitin-proteasome pathway…………………………………...…………..5 1.2 E3 ubiquitin ligases…………..……………………………………………….6 1.3 Members of CRL family……...………………………………………………7 1.4 Members of CRL4……………………………………………………………7 1.5 Function of CRL4B…………..…………….………………………...…….…8 1.6 Cullin KO mice……………..………………………………………….…….10 1.7 Embryogenesis with emphasis on gastrulation……………………….….…..11 1.8 The specific aims and strategy of this study…………………………………12 Chapter 2 Material and method…………………………………………………...…13 2.1 Construction of targeting vector and mice with the loxP-floxed Cul4b allele …….…………………………………………………………………………13 2.2 Generation and genotyping of Cul4b+/∆ female mice and Cul4b KO embryos…….………………………………………………………………..14 2.3 Morphological and Histological Analysis…………………………………...15 2.4 Immunohistochemistry…………...………………………………………….16 2.5 BrdU incorporation of embryos……………………………………………..17 2.6 Measurement of Mitotic index……………………………………………....17 2.7 TUNEL assay……………….……………………………………………….17 2.8 Immunoblotting…………..………………………………………………….18 2.9 Blastocyst outgrowth…….……………………………………….…………19 2.10 Whole-mount in situ hybridization………………………………………….19 Chapter 3 Results………………………………………………………………..……21 3.1 Deletion of Cul4b in (Cul4blox/Y; Prm1-Cre) mice……..……………………21 3.2 Deletion of Cul4b results in early embryonic lethality……………….………22 3.3 Morphological and histological analysis of Cul4b KO embryo……...………22 3.4 Cul4b KO embryos retained epiblast pluripotent marker Oct-3/4 but decreased pluripotent marker Cdx-2 expression in extraembryonic ectoderm……………………………..………………………………………..24 3.5 Cul4b KO embryos retained proliferation capacity and did not increase apoptosis………………………………………..……………………………..25 3.6 CUL4B-specific substrates did not accumulate in Cul4b KO embryos…...….26 3.7 Cul4b KO-deficient blastocysts were defect in proliferation in vitro………...27 3.8 Loss of Cul4b results in abnormal expression pattern of mesoderm marker…………………..……………………………………………………..28 Chapter 4 Discussion………………………………………………………………….30 Section II Cul4b knockout mouse as a potential model for human XLMR…...…..35 摘要……………….………………………………………………….…….…..………36 Abstract………………………………………………………………….…………….37 Chapter 1 Introduction……………………………………………………………….38 1.1 Mutations in CUL4B cause XLMR…………..…………………...…………38 1.2 Substrates of CRL4B………..…………...…………………………………..38 1.3 Mouse model of XLMR.…...………………………………………..………39 1.4 CRL4B mutant mouse as a model for human XLMR………………………40 Chapter 2 Material and method…………………………………………………...…42 2.1 Generation and genotyping of Cul4b-deficient (Cul4b∆/Y) mice………...…42 2.2 Immunoblotting……………………………………………………………..42 2.3 Histology………………………………………………….………………...43 2.4 Immunofluorescence…..………...………………………………….……….44 2.5 Nissl stain……………………………..……………………………………..45 2.6 Golgi stain………………………………………………………...………....45 2.7 Behavioral analysis…….…………………………………...……………….46 2.8 Statistical analysis………..………………………………………………….51 Chapter 3 Results………………………………………………………………..……53 3.1 Deletion of Cul4b in Cul4b∆/Y (Cul4blox/Y; Sox2-Cre) mice…………...……53 3.2 XLMR-like phenotypes in Cul4b∆/Y mice……………..…………….………54 3.3 Expression of CUL4B -related substrates and neuronal markers in the……..… hippocampus…………………………………………………………...……..57 3.4 Reduced dendritic complexity and spine density in the hippocampal neurons of Cul4b∆/Y mice…………….…………………………………………………..60 Chapter 4 discussion………………………………………………………………….63 Section III Conclusion and perspective………………………….………………….71 Figure………………………………………………………………………………….76 Table………………………………………………………………………………….121 Appendix table……………………………………………………………………….125 Appendix …….………………………………………………………………………131 Reference…………………………………………………………………………….147 | |
| dc.language.iso | en | |
| dc.subject | 智能遲緩 | zh_TW |
| dc.subject | 泛素 | zh_TW |
| dc.subject | 胚胎發育 | zh_TW |
| dc.subject | 泛素連結酶 | zh_TW |
| dc.subject | E3 ligase | en |
| dc.subject | ubiquitin | en |
| dc.subject | embryogenesis | en |
| dc.subject | mental retardation | en |
| dc.title | 利用Cullin 4b基因剔除小鼠研究Cullin 4b
在胚胎發育及智能遲緩的角色 | zh_TW |
| dc.title | Utilization of Cullin 4b knockout mice to study the role of Cullin 4b in embryonic development and mental retardation | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 100-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 李立仁(Li-Jen Lee),張淑媛(Sui-Yuan Chang),吳君泰(June-Tai Wu),游麗如(Li-Ru You),楊瑞彬(Ruey-Bing Yang) | |
| dc.subject.keyword | 泛素,泛素連結酶,胚胎發育,智能遲緩, | zh_TW |
| dc.subject.keyword | ubiquitin,E3 ligase,embryogenesis,mental retardation, | en |
| dc.relation.page | 154 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2012-07-30 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 醫學檢驗暨生物技術學研究所 | zh_TW |
| 顯示於系所單位： | 醫學檢驗暨生物技術學系 | |
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