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研究生:蔡育男
研究生(外文):Yu-Nan Tsai
論文名稱:以線蟲為模型探討AIR-2及GSP-2在雄性減數分裂中染色體分離的調控
論文名稱(外文):The Chromosome Segregation is Regulated by AIR-2 and GSP-2 in Caenorhabditis elegans Male Meiosis
指導教授:吳瑞菁
指導教授(外文):Jui-Ching Wu
口試委員:蔡欣祐王齡玉薛雁冰郭靜穎
口試委員(外文):Hsin-Yue TsaiLing-Yu WangYen-Ping HsuehChing-Ying Kuo
口試日期:2023-02-24
學位類別:碩士
校院名稱:國立臺灣大學
系所名稱:醫學檢驗暨生物技術學系
學門:醫藥衛生學門
學類:醫學技術及檢驗學類
論文種類:學術論文
論文出版年:2023
畢業學年度:111
論文頁數:68
中文關鍵詞:雄性減數分裂染色體分離Aurora B蛋白激酶蛋白去磷酸酶染色體轉向
外文關鍵詞:male meiosischromosome segregationAurora B kinasePP1 phosphatasechromosome orientation
DOI:10.6342/NTU202303959
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在細胞的複製過程中,準確且正確的將遺傳物質分離非常重要。若染色體出現異常或數量錯誤,可能導致個體細胞癌化,或在發育前期即死亡;而在生殖細胞中,這種異常則可能導致不孕。許多研究顯示在細胞分裂中,細胞內磷酸化會隨著不同時期的演進而有不同程度的改變。其 中的Aurora B蛋白激酶(Aurora B kinase)藉由磷酸化調控染色體的轉向及分離;同時蛋白去磷酸酶(Protein Phosphatase)拮抗Aurora B蛋白激酶以維持染色體上磷酸化的平衡。
以線蟲為模式生物,在雄性減數分裂中,生殖細胞會進行兩次染色體分離。第一次減數分裂時,同源染色體分離;第二次減數分裂時,姊妹染色分體(sister chromatids)被分配到不同的子細胞。目前仍不清楚在減數分裂中兩次連續的分裂是否與細胞分裂調控機制相同,且兩次分裂為同一套調控機制。我們利用化學及遺傳學的方法,發現在第一次減數分裂AIR-2剔除或是受到抑制時,染色體會發生不規則的排列轉向,且無法進行分離,並且在第二次減數分裂時也觀察到相同現象。暗示著在兩次減數分裂中AIR-2有相同的調控標的。
然而在雄性減數分裂中,我們發現兩次減數分裂中可能是由不同的蛋白去磷酸酶所平衡。在gsp-2 (Protein Phosphatase 1)基因突變的精原母細胞中,染色體在減數分裂的兩次分裂中皆無法在染色體分離前整齊的排列在赤道版上(equatorial template)。利用Protein phosphatase抑制劑okadaic acid 後,染色體也出現與在gsp-2 基因突變的細胞中相似無法在分離前整齊排列的狀況。在第二次減數分裂中,OA抑制劑造成細胞染色體除了排列混亂之外更嚴重的缺陷:例如chromosome bridge及lagging chromosome的現象。由此推斷GSP-2在第一次分裂當中是主要的PP1,而在第二次分裂中則可能還有其他PP1參與蛋白激酶與去磷酸酶之間的調控平衡。
Accurate and precise segregation of chromosome is crucial for ensuring cell integrity during cell division. If happened during mitosis, defective segregation lead to aneuploidy, which subsequently leads to cell death or even cancer. Likewise, in meiosis, mis-segregation results in infertility. During mitotic cell division, Aurora B kinase plays crucial roles in modulating the orientation and separation of chromosomes. PP1 phosphatases counteract Aurora B kinase to maintain proper phosphorylation levels during the dynamic chromosome movements.
In male meiotic cells, two rounds of chromosome separation events take place to separate homologous and then sister chromosomes sequentially. Whether the same Aurora B kinase/phosphatase-dependent phosphorylation is repeated between the two chromosome segregation events during male meiosis remains unclear. Using chemical genetic approaches, we found inhibition of Aurora B kinase AIR-2 in meiosis I caused segregation defects, such as mis-biorientation and nondisjunction, which are comparable to inhibition of Aurora B kinase in meiosis II. These results imply that Aurora B kinase targets the same molecules in both divisions.
In contrast to Aurora B kinase, we found male MI and MII divisions might employ different phosphatases for regulation. Deletion of PP1 GSP-2 caused significant mal-alignment of chromosomes at metaphase onset in MI and the subsequent MII. Primary spermatocytes treated with Pan-PP1 phosphatases inhibitor okadaic acid exhibited chromosome orientation defects comparable to gsp-2 mutants, indicating GSP-2 is the major phosphatase during meiosis I. However, okadaic acid treatment induced a different set of chromosome segregation defects in male meiosis II: chromosomes not only failed to align bi-orientally prior to separation but also showed either chromosome bridge or nondisjunction. These results support that GSP-2 is not the only PP1 involved in the regulation of MII division. Our study reveals Aurora B kinase is regulating MI and MII in a kinase/phosphatase-dependent phosphorylation with different PP1s.
Dissertation acceptance certificate i
誌謝 ii
摘要 iv
Abstract vi
Table of content viii
1 Introduction 1
1.1 A variety of cell division events are controlled by protein phosphorylation status 2
1.2 Chromosome segregation is a balanced act between kinases and phosphatases 5
1.3 Is male meiosis a two-division mitosis or a replicate of female meiosis? 7
1.4 Why is C. elegans taken as a model for investigating male meiotic division? 9
1.5 Examine the role of Aurora B kinase and PP1 phosphatase in two male meiotic division 11
2 Material and Methods 12
2.1 Worm Strains and alleles 12
2.2 Construction of mutant worm strains containing GFP::NDC-80 transgene 12
2.3 Induction of male production 13
2.4 Chemical inhibition assay 14
2.5 Live Imaging microscopy 15
2.6 AIR-2 protein structure prediction and processing 16
2.7 Hybrid AIR-2 repair template construction 16
2.8 Analog-sensitive (as) AIR-2 strain construction 17
2.9 Genotyping of animals 18
2.10 Image analyses and statistical analyses 19
3 Results 20
3.1 AIR-2 is required for chromosome biorientation and separation in meiosis I 20
3.2 Analog-sensitive AIR-2 for meiosis II analysis 22
3.3 AIR-2 is required for chromosome biorientation and separation in meiosis II 25
3.4 GSP-2 is required for chromosome congression and biorientation in meiosis 26
3.5 Okadaic acid induced biorientation and separation defects in male meiosis 29
4 Discussion 32
4.1 Analog-sensitive Aurora B kinase as an approach to study consecutive male meiotic events in C. elegans 32
4.2 AIR-2 dosage differences in MI and MII in C. elegans 34
4.3 Function of PP2A in Caenorhabditis elegans 34
4.4 Do AIR-2 and GSP-2 interact with each other? 36
5 Figures 37
Figure 1. Deletion of the AIR-2 kinase causes chromosome segregation defects 38
Figure 2. Construction of analog-sensitive AIR-2 transgenic strain. 39
Figure 3. AIR-2 is required for meiosis II chromosome segregation 42
Figure 4. GSP-2 is required for chromosome congression and biorientation in meiosis I 44
Figure 5. GSP-2 spermatocytes showed biorientation defect in meiosis II 46
Figure 6. Okadaic acid treated spermatocytes showed biorientation defect in meiosis I 48
Figure 7. Okadaic acid treated spermatocytes showed biorientation defect in meiosis II 50
6 Tables 51
Table 1. Strains generated in this study 51
Table 1.2 Strains from other sources 52
Table 2. Plasmids used in this study 52
Table 3. Oligos used in this study 52
7 Reference 54
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