臺灣博碩士論文加值系統

在胚胎大腦皮質發育時期，神經幹細胞的增生分化及細胞週期的進行與跳出需要被精確調控以確保有適當數量的神經元產生。尿皮質素為神經胜肽促腎上腺皮質素釋放激素中的一員，已知尿皮質素在成體大腦中有許多功能，包含調節壓力反應、神經保護、免疫抑制及生長促進，但是尿皮質素在胚胎時的表現及作用仍不清楚。
在本研究中發現尿皮質素及其接受器表現在發育大腦皮質增生區與神經幹細胞內，因此意味著尿皮質素參與神經幹細胞分裂增生。在胚胎發育時期，尿皮質素mRNA或是蛋白質之表現皆可從E12.5天開始一直持續至出生後第一天，此時也正是大腦皮質發育旺盛之時期。分離胚胎大腦皮質內的神經幹細胞並進行體外培養，發現尿皮質素會降低神經幹細胞增生及自我更新的能力，並且使生長分數及標記指數下降。此外，尿皮質素造成標記指數下降的現象同樣也在ex vivo培養的胚胎大腦皮質中被觀察到。分析神經幹細胞在細胞週期分佈的比例，發現尿皮質素處理的神經幹細胞停留在G0/G1 phase的比例增加，進一步以Ki67蛋白質的表現來區分G0及G1 phase，發現尿皮質素增加神經幹細胞進入G0 phase的比例。此增加的原因有可能是因為尿皮質素促進細胞跳出細胞週期所致。此外，尿皮質素也具有延長G1 phase時間之作用，進而導致進行細胞週期的時間增加。
作用機轉研究中顯示尿皮質素可藉由增加p21的表現，使CDK2活性下降，因而減少Rb磷酸化而造成細胞週期停滯。此外，實驗中也證明尿皮質素具有抑制組織蛋白脫乙醯酶活性的能力，使細胞表現Krüppel-like factor 4 (KLF4)進而活化p21基因的表現。減少KLF4表現可遏阻由尿皮質素誘發之p21限制細胞週期進行的現象。更進一步發現，尿皮質素促使p21表現在跳出細胞週期之神經幹細胞中，並且在分化培養的條件下，可增加神經幹細胞分化成神經細胞的比例。這些結果符合Calegari等人提出的假說，即延長G1 phase時間會促使神經幹細胞離開細胞週期，讓神經幹細胞從增生轉換成分化。因此推論尿皮質素在胚胎大腦皮質中可能作為一種抗分裂素，可與其他生長因子共同調節神經幹細胞增生與分化，促使大腦皮質發育完成。

During corticogenesis, the proliferation and differentiation in neural stem cells are regulated precisely by a balance of extrinsic and intrinsic factors which direct progression into or exit from the cell cycle, and then determine the cortical cytoarchitecture. Urocortin (UCN), a member of the corticotrophin releasing hormone (CRH), is widely expressed in the adult brain and is involved in the functions of neuroprotection, stress response, immune suppression, and dendrite outgrowth. Although limited studies indicate UCN is expressed in the developing cortex, its expression and function are not clear in the embryonic brain. This investigation particularly examined the presence of UCN and its receptors in neural stem cells (NSCs) and clarified the mechanisms underlying the anti-proliferation effect of UCN in NSCs.
This investigation demonstrated that UCN and its receptors CRHR1 and CRHR2 were present in (NSCs). During cortical development, the cortex expressed mRNA and protein from embryonic day 12.5 to postnatal day 1, implying that UCN might be involved in regulation of NSCs proliferation. Treatment of cultured NSCs with UCN reduced cell proliferation, self-renewal potential, growth fraction, and labeling index. The deceased labeling index was also observed in ex vivo cultured brain slice. Flow cytometry analysis revealed that UCN increased the population of NSCs arrested in G0/G1 phase. Ki67 staining for distinguishing these two phases demonstrated that UCN induced more NSCs stayed in G0 phase. This could be the consequence of cell cycle exit induced by UCN. In addition, UCN selectively increased the duration of G1 phase, resulting in prolonging cell cycle progression.
Mechanistic studies in NSCs showed that UCN increased the expression of p21, leading to inactivation of CDK2, and ultmately hypophosphorylation of Rb. Interestingly, UCN directly inhibited histone deacetylase (HDAC) activity, resulting in histone hyperacetylation which transactivated expression of Krüppel-like factor 4 (Klf4) and p21. Knockdown of Klf4 resulted in downregulation of p21-mediated cell-cycling restriction caused by UCN. Furthermore, UCN upregulated p21 in NSCs, thus catalyzing their exit from the cell cycle. Results also showed that UCN promoted neuronal differentiation. These findings are consistent with a previous hypothesis, that lengthening G1 phase of NSCs promotes the switch from proliferation to differentiation, proposed by Calegari et al. These results suggest that UCN might be an anti-mitogen in developing cortex to regulate NSCs proliferation during corticogenesis.

中文摘要………………………………………………………………I
英文摘要………………………………………………………………III
目錄……………………………………………………………………V
圖表目錄………………………………………………………………IX
第一章 緒論
第一節 大腦皮質發育……………………………………………1
第二節 細胞週期………………………………………………2
第三節 細胞週期調控神經幹細胞增殖分化……………………4
第四節 調控因子影響神經幹細胞之細胞週期……………………5
第五節 尿皮質素及其接受器於腦區之分佈與功能……………8
第六節 尿皮質素及其接受器在胚胎腦中的表現………………10
第七節 研究動機與目標…………………………………………10
第二章 實驗材料與方法
第一節 大腦皮質神經球體培養…………………………………12
第二節 細胞增生試驗…………………………………………13
第三節 神經幹細胞自我更新試驗(Self-renewal assay)………14
第四節 細胞免疫染色……………………………………………15
第五節 組織免疫染色……………………………………………16
第六節 大腦皮質組織型培養(Organotypic culture)……………17
第七節 Bromodeoxyuridine incorporation免疫染色………………18
第八節 細胞分化測試…………………………………………………18
第九節 尿皮質素螢光標記………………………………………18
第十節 細胞週期動態測量………………………………………20
第十一節 Terminal deoxynucleotide transferase-mediated UTP nick end labeling (TUNEL)分析………………………………………………………22
第十二節 西方點墨法……………………………………………22
第十三節 酵素聯結免疫吸附分析法…………………………24
第十四節 即時反轉錄-聚合酶連鎖反應(Real-time Reverse Transcription-Polymerase Chain Reaction, RT-PCR)………………………………………25
第十五節 干擾RNA轉染………………………………………26
第十六節 冷光活性試驗…………………………………………27
第十七節 激酶活性試驗…………………………………………28
第十八節 流式細胞儀分析………….……………………………29
第十九節 組織蛋白脫乙醯酶活性試驗…………………………29
第二十節 統計分析………………………………………………30
第三章 實驗結果
第一節 尿皮質素及其接受器在胚胎大腦皮質中的表現………31
第二節 尿皮質素及其接受器在培養的神經幹細胞中之表現…32
第三節 尿皮質素降低神經幹細胞增生…………………………32
第四節 尿皮質素降低神經幹細胞之生長分數及標記指數……33
第五節 尿皮質素降低大腦皮質切片中之神經幹細胞的增生…34
第六節 尿皮質素阻止神經幹細胞進入S phase………………35
第七節 尿皮質素增加神經幹細胞進入G0 phase……………36
第八節 尿皮質素經由增加G1 phase時間使細胞週期延長…36
第九節 尿皮質素促進神經幹細胞跳出細胞週期……………37
第十節 尿皮質素增進p21-Rb訊息傳遞而造成細胞分裂比例下降…38
第十一節 尿皮質素增進p21表現促使神經幹細胞跳出細胞週期…40
第十二節 尿皮質素抑制組織蛋白脫乙醯酶活性參與了p21調控之抑制增生作用……41
第十三節 尿皮質素抑制組織蛋白脫乙醯酶活性可促進KLF4表現，進而轉錄活化p21表現……………44
第十四節 KLF4參與調控神經幹細胞增生………………………45
第十五節 尿皮質素促進神經幹細胞分化………………………45
第十六節 尿皮質素表現在E16.5天大腦皮質之已分化區………46
第四章 討論
第一節 尿皮質素在發育大腦皮質中可做為一種抗分裂素……47
第二節 尿皮質素對細胞週期動態之影響……………………49
第三節 p21調控細胞週期………………………………………51
第四節 p21促使細胞跳出細胞週期……………………………53
第五節 組織蛋白脫乙醯酶調控神經幹細胞增生與分化………55
第六節 組織蛋白脫乙醯酶與KLF4及p21之間的關係……………57
第七節 總結………………………………………………………58
第五章 未來展望………………………………………………………59
第六章 參考文獻…………………………………………………61

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