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完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 陳小梨(Show-Li Chen) | |
dc.contributor.author | Yi-Wen Chen | en |
dc.contributor.author | 陳怡雯 | zh_TW |
dc.date.accessioned | 2021-06-16T02:33:31Z | - |
dc.date.available | 2017-09-25 | |
dc.date.copyright | 2015-09-25 | |
dc.date.issued | 2015 | |
dc.date.submitted | 2015-07-28 | |
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dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/53922 | - |
dc.description.abstract | BCAS2 (breast carcinoma amplified sequence 2)是一個26 kD的核蛋白,在乳癌細胞株MCF-7和BT-20有表現量上升的現象。我們實驗室的研究發現,BCAS2是抑癌蛋白p53的負調控者,透過與p53的作用影響細胞生長。此外,BCAS2會增加前列腺癌細胞中,雄激素受體mRNA和蛋白質的表現量,進而促進癌細胞發展。BCAS2會參與形成核醣核酸剪切體Prp19/CDC5L complex,幫助pre-mRNA剪切,而Delta基因為其剪切目標之一;另外,BCAS2亦是果蠅發育所必需的基因。
先前在外顯子微陣列(exon array)分析中,我們發現在MCF-7細胞株默化BCAS2,會造成β-catenin表現量下降。β-Catenin是Wnt/β-catenin訊息傳遞路徑重要的參與者。先前研究發現,在阿茲海默症等神經退化性疾病,Wnt/β-catenin訊息傳遞路徑有異常的現象。另有微陣列晶片的研究指出,阿茲海默症患者的BCAS2 RNA有表現量下降的情形;此外,BCAS2所在基因座的基因多型性可能與自閉症相關。已有諸多文獻報導,Wnt/β-catenin訊息傳遞路徑會調控成體神經新生(adult neurogenesis)。因此在本篇研究中,我們想探討BCAS2在成體神經新生所扮演的角色。神經幹細胞存在哺乳類動物前腦的兩個區域,故具有成體神經新生的能力;一為海馬迴(hippocampus)中,dentate gyrus (DG)的subgranular zone (SGZ),二為側腦室(lateral ventricle)的subventricular zone (SVZ)。 透過小鼠前腦切片染色,我們發現BCAS2會表現在整個前腦的細胞核中;特別在具有成體神經新生功能的海馬迴,位於SGZ的神經幹細胞(Sox2+)、DG內層的神經母細胞或未成熟神經細胞(Dcx+),及成熟神經細胞(NeuN+)皆會表現BCAS2。此結果暗示,BCAS2可能參與海馬迴的成體神經新生。接著,我們使用條件式基因剔除小鼠(CaMKIIα-Cre; BCAS2Flox/Flox),探討小鼠出生後,專一性剔除前腦BCAS2對成體神經新生的影響。實驗結果顯示,條件式剔除BCAS2會造成DG體積變小、神經幹細胞數目減少,及未成熟神經細胞的神經纖維發育異常。以溴脫氧尿核苷(BrdU)標定新生細胞的結果也顯示,條件式基因剔除小鼠的增殖神經幹細胞(proliferating neural stem cells)數目減少、未成熟神經細胞分化能力較差以及新生神經細胞數量減少;此外,透過kainic acid刺激神經前驅細胞增殖,我們認為BCAS2確實會參與海馬迴成體神經新生。最後,我們發現BCAS2與β-catenin會同時表現在DG內層的神經細胞中,並且在條件式基因剔除小鼠的海馬迴中,β-catenin的表現量較低。此結果暗示BCAS2可能調控β-catenin的剪切,進而影響成體神經新生。 | zh_TW |
dc.description.abstract | Breast carcinoma amplified sequence 2 (BCAS2) is a 26 kD nuclear protein, which has been reported to upregulate in breast cancer cell lines MCF-7 and BT-20. Currently, we demonstrate that BCAS2 is a p53 negative regulator and involves in cell growth regulation. Additionally, BCAS2 promotes prostate cancer cells proliferation by enhancing androgen receptor (AR) mRNA transcription and protein stability. On the other hand, BCAS2 is a component of Prp19/CDC5L core splicing complex and Delta gene is its splicing targeted gene. We also found that BCAS2 is an essential gene for Drosophila development.
Our unpublished data showed that the expression of β-catenin was decreased in the BCAS2 depletion exon array analysis. β-Catenin is a crucial effector in Wnt/β-catenin signaling pathway. Wnt/β-catenin signaling is reportedly impaired in several neurodegenerative diseases such as Alzheimer’s disease (AD). Moreover, microarray analysis in AD patients reduces the RNA expression of BCAS2 compared to normal healthy. Also, genetic variants on 1p13.2, covering BCAS2 gene loci is associated with autism. Due to the Wnt/β-catenin signaling reportedly involves in adult neurogenesis. Therefore, we were interested to investigate the role of BCAS2 in the adult neurogenesis. In this study, we found that BCAS2 was expressed in the nuclei in the entire forebrain, including hippocampus and cortex. In hippocampal dentate gyrus (DG), BCAS2 expression presented in subgranular zone (SGZ) and granule cell layer (GCL); also co-localized with Sox2 (neural stem cell of SGZ) and NeuN (mature neuron of granule cell layer) indicating that BCAS2 may involve in adult neurogenesis. Furthermore, we used BCAS2 conditional knockout mice (CaMKIIα-Cre; BCAS2Flox/Flox) to investigate the effect of depleting BCAS2 in adult neurogenesis. The results showed the reduction of DG volume by measuring NeuN cells in cKO compared to its counterpart of wild-type (WT). Plus, the declined number of Sox2-staining NSCs and disruption of DCX-staining dendrite development in immature neurons were shown in cKO mice compared with WT. Moreover, the BrdU-labeling experiments were conducted and cKO mice displayed the decreased NSCs, the maturation rate of immature neurons, and the number of newborn granule cells compared to WT. BCAS2-involved in adult neurogenesis could be further confirmed by kainic acid (KA) stimulation. The mechanism of BCAS2-participating in the adult neurogenesis may be due to that BCAS2 regulated β-catenin splicing. Our results showed that BCAS2 co-expressed with β-catenin in the inner cell layer of DG by immunofluorescence assay, and the expression of β-catenin was declined in the hippocampal DG of cKO mice compared to WT. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T02:33:31Z (GMT). No. of bitstreams: 1 ntu-104-R02445131-1.pdf: 5585493 bytes, checksum: ca0447d01d8777f74d118cca9728d2a9 (MD5) Previous issue date: 2015 | en |
dc.description.tableofcontents | 致謝 iii
中文摘要 iv Abstract vi Chapter 1 Introduction 1 1.1 BCAS2 and cancer 1 1.2 BCAS2 and splicing 2 1.3 Wnt/β-catenin signaling pathway 2 1.4 Wnt/β-catenin signaling in neuronal degenerative diseases 3 1.5 Wnt/β-catenin signaling in adult neurogenesis 4 1.6 The correlation between BCAS2 and neuronal degenerative diseases 5 Chapter 2 MATERIALS AND METHODS 8 2.1 Mice cohorts 8 2.2 Western blot analysis 8 2.3 Tissue preparation 9 2.4 Immunohistochemistry 9 2.5 BrdU administration 11 2.6 Kainic acid administration 12 2.7 Stereological analysis 12 2.8 Statistical analysis 13 Chapter 3 RESULTS 14 3.1 The expression pattern of BCAS2 in the mouse forebrain. 14 3.2 The co-localization of BCAS2 and neuronal markers in the forebrain of mice. 15 3.3 The Cre expression pattern with Sox2 and NeuN in CaMKIIα-Cre transgenic mice. 16 3.4 The reduction of DG volume of BCAS2 cKO mice. 17 3.5 The reduction of NSC number and dendrite development in the DG of BCAS2 cKO mice. 19 3.6 The role of BCAS2 in Sox2 stem cell pool and proliferation at adult neuron. 21 3.7 The reduction of differentiation rate and newborn neurons in BCAS2 cKO mice. 22 3.8 The reduction synthesis of newborn neurons in BCAS2 cKO mice. 23 3.9 The correlation of BCAS2 and Delta in the hippocampus of mice. 24 3.10 The correlation of BCAS2 and β-catenin in the DG of mice. 24 Chapter 4 DISCUSSION 26 REFERENCES 32 FIGURES 39 | |
dc.language.iso | en | |
dc.title | BCAS2在成體神經新生過程之角色 | zh_TW |
dc.title | The Role of BCAS2 in Adult Neurogenesis | en |
dc.type | Thesis | |
dc.date.schoolyear | 103-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 黃怡萱(Yi-Shuian Huang),李立仁(Li-Jen Lee) | |
dc.subject.keyword | BCAS2,成體神經新生,Wnt/β-catenin訊息傳遞路徑,條件式基因剔除小鼠(CaMKIIα-Cre,BCAS2Flox/Flox), | zh_TW |
dc.subject.keyword | BCAS2,adult neurogenesis,Wnt/β-catenin signaling,BCAS2 cKO mice (CaMKIIα-Cre,BCAS2Flox/Flox), | en |
dc.relation.page | 55 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2015-07-28 | |
dc.contributor.author-college | 醫學院 | zh_TW |
dc.contributor.author-dept | 微生物學研究所 | zh_TW |
顯示於系所單位: | 微生物學科所 |
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