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研究生:李明洋
研究生(外文):Li, Ming-Yang
論文名稱:TRIP6透過YAP調控出生後小鼠側腦室-嗅球路逕上神經幹細胞的特性以及醫學上可能的應用
論文名稱(外文):YAP Mediates TRIP6-Promoted Neural Stem Cell Maintenance in the Postnatal Mammalian Subventricular Zone-Olfactory Pathway and Its Applications
指導教授:王慈蔚
指導教授(外文):Wang, Tsu-Wei
學位類別:博士
校院名稱:國立臺灣師範大學
系所名稱:生命科學系
學門:生命科學學門
學類:生物學類
論文種類:學術論文
論文出版年:2019
畢業學年度:107
語文別:英文
論文頁數:183
中文關鍵詞:神經幹細胞出生後神經元新生TRIP6YAPginkgolide B
外文關鍵詞:neural stem cellspostnatal neurogenesisTRIP6YAPginkgolide B
相關次數:
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  • 收藏至我的研究室書目清單書目收藏:1
出生後的哺乳動物腦中有持續的神經元新生,分別發生在海馬迴齒狀迴,以及側腦室下區到嗅球的路徑上。報導指出內生性的神經幹細胞有治療腦傷或神經退化性疾病的潛力,研究調控神經幹細胞的因子和機制因此有醫學上的應用價值。已知神經幹細胞的特性受到多種因子調控,然而TRIP6、YAP以及銀杏萃取物ginkgolide B等對於出生後哺乳動物神經幹細胞的影響仍是未知的。TRIP6的蛋白質結構具有三個LIM區位,可以和多種蛋白質進行交互作用而調控細胞增生、存活及移動。我們發現TRIP6不表現在會移動的神經母細胞中,而表現在神經幹細胞中。TRIP6促進神經幹細胞的維持、增生,並且抑制分化。且促進神經幹細胞自我更新的Notch訊息傳遞路徑能被TRIP6活化。Hippo訊息傳遞路徑藉由抑制YAP來調控細胞增生,控制器官大小。我們發現TRIP6透過PP1A來抑制Hippo訊息傳遞路徑,活化YAP。並且TRIP6透過YAP來促進神經幹細胞的維持、增生,以及抑制分化。在神經幹細胞的分化上,我們則發現ginkgolide B透過Wnt訊息傳遞路徑促進神經元新生。我們這一系列的研究指出TRIP6透過YAP維持神經幹細胞的特性,而給予ginkgolide B則可以促進神經元新生。
Postnatal neurogenesis in the dentate gyrus and subventricular zone (SVZ)-olfactory bulb pathway in mammals is regulated by extrinsic and intrinsic factors. Since endogenous neural stem cells (NSCs) in the adult brain have potential to treat neurodegenerative disorders, studying mechanisms regulating postnatal NSCs may provide clinical applications. However, the role of TRIP6, YAP and ginkgolide B in postnatal NSCs remain unclear. TRIP6 belongs to zyxin family of LIM proteins, which have been shown to interact with various proteins to regulate cell proliferation, survival and migration. We find that TRIP6 is expressed by adult NSCs in the SVZ but not migrating neuroblasts. TRIP6 is necessary and sufficient for self-renewal and proliferation of adult NSCs, but inhibits their differentiation. We also find that TRIP6 activates the Notch signaling, a pathway required for NSC self-renewal. Previous studies show that the Hippo pathway regulates cell proliferation and organ size through inhibiting YAP. We find that TRIP6 inhibits the Hippo pathway and activates YAP through PP1A. TRIP6 promotes NSC maintenance and proliferation and inhibits neuronal differentiation through YAP. During differentiation of NSCs, we also find that ginkgolide B promotes neurogenesis through the Wnt pathway. These findings show that YAP acts downstream of TRIP6 to promote adult NSC maintenance, whereas ginkgolide B promotes neurogenesis in the postnatal NSCs.
Abstract in Chinese 7

Abstract 9

Chapter one: Introduction 10
1. Postnatal neurogenesis 10
2. Methods to study postnatal NSCs 10
3. The NSC niche and extrinsic factors 13
4. Intrinsic factors 14
5. Potential functions of postnatal neurogenesis 15
6. Aims of the thesis 17
7. References 18


Chapter two: TRIP6 Regulates Neural Stem Cell Maintenance in the Postnatal Mammalian Subventricular Zone 25
1. Abstract 26
2. Introduction 27
3. Materials and methods 30
3.1 Animals
3.2 Plasmids
3.3 Fixation and sectioning
3.4 RT-PCR
3.5 NIH3T3 cell culture
3.6 Immunoblotting
3.7 Immunofluorescence
3.8 Neurosphere culture and electroporation
3.9 Transfection and differentiation of NSCs
3.10 Luciferase assay
3.11 Statistical analysis
4. Results 38
4.1 TRIP6 is expressed by NSCs in the embryonic and adult mouse brain
4.2 TRIP6 maintains self-renewal and proliferation of NSCs
4.3 TRIP6 inhibits differentiation of postnatal NSCs
4.4 TRIP6 activates the Notch signaling pathway
5. Discussion 46
6. References 50
7. Figures 59


Chapter three: YAP Mediates TRIP6-Promoted Neural Stem Cell Maintenance in the Postnatal Mammalian Subventricular Zone-Olfactory Pathway 72
1. Abstract 73
2. Introduction 74
3. Materials and methods 77
3.1 Animals
3.2 Fixation and sectioning
3.3 Plasmids
3.4 Primary NSC cultures
3.5 Immunofluorescence
3.6 P19 cell culture
3.7 HEK293T cell culture
3.8 Co-immunoprecipitation
3.9 Western blot analysis
3.10 Luciferase assay
3.11 Image acquisition and statistical analysis
4. Results 86
4.1 YAP is necessary and sufficient for self-renewal in postnatal NSCs
4.2 YAP promotes cell proliferation in postnatal NSCs
4.3 YAP inhibits differentiation in postnatal NSCs
4.4 YAP is important for the maintenance and proliferation of NSCs
4.5 TRIP6 induces the transcription activity of YAP through inhibiting LATS
4.6 TRIP6 recruits PP1A to inhibit the phosphorylation of LATS1
4.7 TRIP6 promotes stem cell maintenance in postnatal NSCs through YAP
5. Discussion 98
6. References 103
7. Figures 111


Chapter four: Ginkgolide B Promotes Neuronal Differentiation Through the Wnt/β-catenin Pathway in Neural Stem Cells of the Postnatal Mammalian Subventricular Zone 131
1. Abstract 132
2. Introduction 133
3. Materials and methods 136
3.1 Chinese herbal medicines
3.2 P19 cell culture
3.3 Primary NSC cultures
3.4 Plasmid for knockdown experiments
3.5 Immunofluorescence
3.6 Nuclear fractionation
3.7 Western blot
3.8 Luciferase assay
3.9 Image and statistical analysis
4. Results 142
4.1 GBE promotes neuronal differentiation in P19 cells.
4.2 GBE promotes neuronal differentiation in postnatal NSCs.
4.3 GB promotes neuronal differentiation in postnatal NSCs.
4.4 GB increases the level of nuclear β-catenin and activates the Wnt pathway.
4.5 GB promotes neuronal differentiation through the Wnt pathway in postnatal NSCs.
5. Discussion 150
6. References 154
7. Figures 162


Chapter five: Discussion 171
1. Summary of the thesis work 171
2. TRIP6 and NSC anchoring 171
3. Mechanical force and YAP activity in postnatal NSCs 172
4. Clinical applications I: YAP and induced pluripotent stem (iPS) cells 173
5. Clinical applications II: TRIP6, YAP and tumor progression 174
6. Future direction I: TRIP6 and the Notch pathway 175
7. Future direction II: YAP and the Shh pathway 175
8. Future direction III: TRIP6, NSC anchoring and the Notch pathway 176
9. Conclusion 178
10. References 179
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Chapter five:

Achanta, P., Capilla-Gonzalez, V., Purger, D., Reyes, J., Sailor, K., Song, H., Garcia-Verdugo, J.M., Gonzalez-Perez, O., Ford, E., and Quinones-Hinojosa, A. (2012). Subventricular zone localized irradiation affects the generation of proliferating neural precursor cells and the migration of neuroblasts. Stem Cells 30, 2548-2560.
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Lv, K., Chen, L., Li, Y., Li, Z., Zheng, P., Liu, Y., Chen, J., and Teng, J. (2015). Trip6 promotes dendritic morphogenesis through dephosphorylated GRIP1-dependent myosin VI and F-actin organization. J Neurosci 35, 2559-2571.
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Ming, G.L., and Song, H. (2011). Adult neurogenesis in the mammalian brain: significant answers and significant questions. Neuron 70, 687-702.
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