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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/60124完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳小梨 | |
| dc.contributor.author | Chu-Wei Huang | en |
| dc.contributor.author | 黃楚崴 | zh_TW |
| dc.date.accessioned | 2021-06-16T09:57:39Z | - |
| dc.date.available | 2018-03-01 | |
| dc.date.copyright | 2017-03-01 | |
| dc.date.issued | 2016 | |
| dc.date.submitted | 2016-12-15 | |
| dc.identifier.citation | Part I:
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/60124 | - |
| dc.description.abstract | Part I:
BCAS2 是一個26 kDa 的核蛋白。近來的研究發現至少有兩種與BCAS2 相關的致癌機制：(1) BCAS2 作為p53 的負調控者:抑制BCAS2 的表現會造成p53 野生型細胞株的細胞凋亡，而在不具有p53 或是p53 突變型的細胞株中，抑制BCAS2的表現會造成細胞生長週期停滯在G2/M 時期。(2) 與hPrp19 complex 中負責DNA修復機制有關的單股DNA 結合蛋白結合，參與DNA 受損反應的機制中。另外，BCAS2 是調控RNA 剪切的hPrp19 complex 裡的主要核心成員之一。我們過去的 研究發現，由於BCAS2 與Delta pre-mRNA 剪切及與Delta-Notch 訊息傳遞有關，在果蠅翅膀中抑制BCAS2 的表現會透過造成其發育缺陷。在本篇研究中，我們首先利用exon array assay 篩選表現量會受到抑制BCAS2 影響的基因，其中我們發現β-catenin 是BCAS2 調控RNA 剪切時的下游目標之一。許多文獻證實β-catenin 與神經樹突生長發育的調控有關，因此，我們我們利用條件式基因剔除小鼠將前腦中的BCAS2 剔除，藉此探討BCAS2 在樹突生長中所扮演的生長中所扮演的角色。在BCAS2 條件式基因剔除小鼠中我們發現其有類似小腦症 (microcephaly) 的症狀產生，同時我們也發現齒狀迴的體積縮小，另外，在莫氏水迷宮以及被動避險的實驗也發現到學習記憶能力的減退。高基氏染色法亦顯示在BCAS2 條件式基因剔除小鼠的齒狀迴中，神經細胞的樹突長度、複雜度以及樹突棘密度都有顯著減少。此外，利用DCX 及Brdu 染色標記染色齒狀迴中新生細胞的方式也發現了樹突生長較差的現象。為了更進一步探討BCAS2 經由何種機制造成樹突的生長缺失，我們將β-catenin 大量表現於BCAS2 默化的初級神經元中，發現β-catenin 可使BCAS2 默化造成的樹突生長缺失有顯著回復。綜上所述，BCAS2 為β-catenin 之上游調控者，可透過調控β-catenin 的表現量在樹突生長過程中扮演重要的角色。 Part II: 在先前的研究結果中顯示，在前腦剔除BCAS2表現後會造成神經樹突的畸形以及學習記憶能力的缺失。同時，BCAS2可作為β-catenin上游的調控因子，在神經樹突的生長過程中至少有部分會透過BCAS2對於β-catenin的調控。BCAS2在整個前腦中幾乎都會表現。怡雯的論文中指出，BCAS2條件式剔除小鼠的齒狀迴有明顯變小的現象。在本論文的第一部份中，我們發現前腦剔除BCAS2之後除了會造成神經樹突畸形之外，也觀察到前腦重量顯著小少及外型有變小的趨勢。因此，我們想要更深入的探究BCAS2條件式剔除小鼠所表現出的小腦症症狀。首先，藉由螢光染色的方式，我們確認了在BCAS2條件式剔除小鼠中，除了齒狀迴之外，BCAS2的表現在前腦的其他區域，包括皮質，都能被有效剔除。另外，BCAS2條件式剔除小鼠有明顯較低的腦部身體身體質量比，這也是一個小腦症的主要症狀。再者，失去了BCAS2的表現會造成大腦皮層的厚度減少以及減少以及神經細胞的縮小但其總量不變。總結上述的實驗結果，BCAS2條件式剔除小鼠會表現出繼發性小腦症的症狀。而這也許可作為一個研究出生後腦部發育以及相關神經疾病的有用工具。 | zh_TW |
| dc.description.abstract | Part I:
Breast carcinoma amplified sequence 2 (BCAS2) is a 26 kDa nuclear protein.Recent studies demonstrated that there were at least two BCAS2 mechanisms involved in carcinogenesis: (1) BCAS2 is a negative regulator of p53: Deprivation of BCAS2 causes apoptosis in p53 wild-type cell lines but leads G2/M arrest in p53 null and p53 mutant cell lines; (2) binding to a single-stranded DNA-binding protein associated with the DNA repair function of the hPrp19 complex, which involves in the DNA damage response. In addition, BCAS2 is a core component of the hPrP19 complex that controls RNA splicing. Our previous studies revealed that wing-specific knockdown of BCAS2 leads to Drosophila wing developmental defects, which result from the participation of BCAS2 in Delta pre-mRNA splicing and regulation of Delta-Notch signaling. Here, we performed an exon array assay and showed that β-catenin is a target of BCAS2 splicing regulation. The regulation of dendrite growth and morphology by β-catenin is well documented. Therefore, we generated conditional knockout (cKO) mice to eliminate the BCAS2 expression in the forebrain to investigate the role of BCAS2 in dendrite growth. BCAS2 cKO mice showed a microcephaly-like phenotype with a reduced volume in the dentate gyrus (DG) and low levels of learning and memory, as evaluated using Morris water maze analysis and passive avoidance, respectively. Golgi staining revealed shorter dendrites, less dendritic complexity and decreased spine density in the DG of BCAS2 cKO mice. Moreover, the cKO mice displayed a short dendrite length in newborn neurons labeled by DCX, a marker of immature neurons, and BrdU incorporation. To further examine the mechanism underlying BCAS2-mediated dendritic malformation, we overexpressed β-catenin in BCAS2-depleted primary neurons and found that the dendritic growth was restored. In summary, BCAS2 is an upstream regulator of β-catenin gene expression and plays a role in dendrite growth at least partly through β-catenin. Part II: Previously we characterized that BCAS2 is an upstream regulator for β-catenin gene splicing; and plays a role in dendritic growth at least partly through β-catenin using conditional depletion of BCAS2 in the forebrain (named BCAS2 cKO). BCAS2 cKO mice show a reduction of dentate gyrus (DG) volume. To extensively characterize the volume of cortex in BCAS2 cKO that were driven by CaMKII-Cre, we found that depletion of BCAS2 could cause a reduction ratio of forebrain weight to body weight in comparison to WT; suggesting a microcephaly phenotype. IFA analysis of BCAS2 cKO revealed that BCAS2 expression was not only diminished in DG but also in other forebrain regions including cortex, striatum, thalamus and hypothalamus. The deprivation of BCAS2 caused the reduction of somatosensory cortical thickness (chosen from a range of bregma -1.45 mm to -1.68 mm) and pyramidal neuronal size in layer V. However the pyramidal neuron number was comparable in comparison to wt, however the density of neuron was higher in cKO than control. Taken together, BCAS2 cKO mice exhibit the reduced cortex volume. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-16T09:57:39Z (GMT). No. of bitstreams: 1 ntu-105-D99445009-1.pdf: 8685058 bytes, checksum: 42282dafaa7ebe48ddcb01bed46e080d (MD5) Previous issue date: 2016 | en |
| dc.description.tableofcontents | 口試委員審定書 I
致謝 II PART I: CONDITIONAL KNOCKOUT OF BREAST CARCINOMA SEQUENCE 2 (BCAS2) IN MOUSE FOREBRAIN CAUSES DENDRITIC MALFORMATION VIA Β-CATENIN III 中文摘要 IV ABSTRACT V CHAPTER 1 1 1.1 INTRODUCTION 1 1.1.1 THE MAIN FUNCTIONS OF BCAS2 IN CANCERS AND RNA SPLICING 1 1.1.2 THE ROLE OF PRP19 SPLICEOSOME COMPLEX AND BCAS2 IN DEVELOPMENTAL PROCESS. 2 1.1.3 THE RELATIONSHIP OF SPLICING FACTORS AND NEURODEGENERATIVE DISEASE. 2 1.1.4 WNT/Β-CATENIN SIGNALING IN NEURODEGENERATIVE DISEASES. 3 1.1.5 AIM OF THIS STUDY. 4 CHAPTER 2 5 1.2 MATERIALS AND METHODS 5 1.2.1 EXON ARRAY ANALYSIS 5 1.2.2 CONSTRUCTION OF A TARGETING VECTOR AND BCAS2-FLOXED MICE 5 1.2.3 GENERATION AND GENOTYPING OF BCAS2 CONDITIONAL KNOCKOUT MICE 6 1.2.4 IMMUNOHISTOCHEMISTRY (IHC) AND IMMUNOFLUORESCENCE ASSAY (IFA) 6 1.2.5 GOLGI STAINING 7 1.2.6 DG VOLUME ANALYSIS 7 1.2.7 DENDRITE GROWTH 7 1.2.8 BEHAVIORAL TESTS 8 1.2.9 WESTERN BLOT ANALYSIS 9 1.2.10 RT-PCR AND QUANTITATIVE PCR 9 1.2.11 CELL CULTURE AND TRANSFECTION 9 1.2.12 STATISTICAL ANALYSIS 10 1.2.13 PRIMER AND RNAI TARGET SEQUENCES LIST 11 1.2.14 ANTIBODY LIST 12 CHAPTER 3 13 1.3 RESULTS 13 1.3.1 EXPRESSION OF Β-CATENIN IS REGULATED BY BCAS2 VIA PRE-MRNA SPLICING 13 1.3.2 BCAS2 DISTRIBUTION IN BRAIN 14 1.3.3 GENERATION OF FOREBRAIN-SPECIFIC BCAS2 KO MICE 15 1.3.4 BCAS2 CKO IN THE MOUSE FOREBRAIN CAUSES A MICROCEPHALY-LIKE PHENOTYPE 16 1.3.5 BCAS2 CKO MICE SHOW IMPAIRED COGNITIVE BEHAVIORS 17 1.3.6 BCAS2 CKO IN MICE RESULTS IN DENDRITIC MALFORMATION 18 1.3.7 BCAS2 CKO MICE HAVE REDUCED DENDRITE GROWTH IN THE NEWBORN NEURONS OF THE ADULT DG 19 1.3.8 EXPRESSION OF β-CATENIN IS REDUCED IN BCAS2 CKO MICE 20 1.3.9 OVEREXPRESSION OF β-CATENIN CAN RESCUE DENDRITIC GROWTH IN BCAS2-KNOCKDOWN PRIMARY NEURONS 21 CHAPTER 4 24 1.4 DISCUSSION 24 CHAPTER 5 29 1.5 FIGURES AND TABLES 29 REFERENCES 59 PART II: CONDITIONAL KNOCKOUT OF BCAS2 CAUSES MICROCEPHALY-LIKE PHENOTYPE 66 中文摘要 67 ABSTRACT 68 CHAPTER 1 69 2.1 INTRODUCTION 69 2.1.1 THE DEVELOPMENT OF BRAIN AND THE ORGANIZATION OF CEREBRAL CORTEX 69 2.1.2 MICROCEPHALY 70 2.1.3 THE RELATIONSHIP BETWEEN BRAIN SIZE AND COGNITIVE FUNCTION 71 2.1.4 AIM OF THIS STUDY 72 CHAPTER 2 73 2.2 MATERIALS AND METHODS 73 2.2.1 IMMUNOHISTOCHEMISTRY (IHC) AND IMMUNOFLUORESCENCE ASSAY (IFA) 73 2.2.2 STEREOLOGICAL ANALYSIS 74 2.2.3 STATISTICAL ANALYSIS 75 CHAPTER 3 76 2.3 RESULTS 76 2.3.1 THE ACTIVITY OF CAMKIIΑ-ICRE IN DIFFERENT BRAIN REGIONS OF BCAS2 CKO MICE. 76 2.3.2 BCAS2 CKO MICE SHOW MICROCEPHALY-LIKE PHENOTYPE. 76 2.3.3 DEPLETION OF BCAS2 CAUSES DECREMENT OF CORTICAL THICKNESS. 77 CHAPTER 4 80 2.4 DISCUSSION 80 2.4.1 FUTURE PLANS 82 CHAPTER 5 85 2.5 FIGURES 85 REFERENCE 94 APPENDIX 100 | |
| dc.language.iso | en | |
| dc.subject | BCAS2 | zh_TW |
| dc.subject | 樹突畸形 | zh_TW |
| dc.subject | 皮質 | zh_TW |
| dc.subject | 樹突生長 | zh_TW |
| dc.subject | 小腦症 | zh_TW |
| dc.subject | β-catenin | zh_TW |
| dc.subject | p53 | zh_TW |
| dc.subject | microcephaly | en |
| dc.subject | BCAS2 | en |
| dc.subject | dendrite growth | en |
| dc.subject | β-catenin | en |
| dc.subject | cortex | en |
| dc.subject | p53 | en |
| dc.subject | dendritic malformation | en |
| dc.title | 條件式剔除小鼠前腦之BCAS2 導致小腦症 | zh_TW |
| dc.title | Conditional knockout of BCAS2 in mouse forebrain causes microcephaly | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 105-1 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 王培育,潘俊良,黃怡萱,鄭菡若 | |
| dc.subject.keyword | BCAS2,p53,β-catenin,小腦症,樹突生長,皮質,樹突畸形, | zh_TW |
| dc.subject.keyword | BCAS2,p53,β-catenin,microcephaly,dendrite growth,cortex,dendritic malformation, | en |
| dc.relation.page | 115 | |
| dc.identifier.doi | 10.6342/NTU201603795 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2016-12-16 | |
| 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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