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Please use this identifier to cite or link to this item: http://ntour.ntou.edu.tw:8080/ir/handle/987654321/30194

Title: HIF2 alpha 在斑馬魚胚胎發育時期整合中樞神經系統的存活及分化
Integration of CNS survival and differentiation by HIF2α
Authors: Ching-Yi Ko
柯靜宜
Contributors: NTOU:Institute of Bioscience and Biotechnology
國立臺灣海洋大學:生物科技研究所
Keywords: 低氧誘發蛋白2α;生存素;神經前驅細胞;細胞凋亡;分化
HIF2α;survivin;neural progenitor cells;apoptosis;differentiation
Date: 2011
Issue Date: 2011-11-25T07:36:19Z
Abstract: 摘要 低氧誘發因子(Hypoxia inducible factor, HIF)之HIF1α及HIF2α 和survivin是人類許多癌症中重要的標識基因。且在胚胎發育時期,它們普遍表現在各種組織及細胞中,其中包含了中樞神經系統。然而,我們對於它們在胚胎中的功能卻鮮少知道。在本篇研究中驗證了在斑馬魚胚胎發育過程中,HIF2α保護神經前驅細胞及神經分化的過程,主要是藉由促進調控下游基因survivin 之兩個同源基因birc5a 及 birc5b的轉錄機制所致。利用Morpholino將HIF2α弱化會降低birc5a 及 birc5b的轉錄作用,並且造成非p53依賴性的大量細胞凋亡以及神經細胞發育停止的現象。再者,birc5a 及 birc5b被抑制亦會造成類似的缺陷情況,將兩者弱化後所導致的神經發育缺陷與hif2α弱化的胚胎所引起的缺陷相似。外源性的birc5a 及 birc5b mRNAs可以救回部分因HIF2α弱化所造成的損害,顯示出Birc5a 及 Birc5b扮演HIF2α的下游基因的角色。此外,將hif2α,birc5a 及 birc5b個別弱化,在殘存的神經先驅細胞內會致使cdk 抑制子,如: p27/cdkn1b 與 p57/cdkn1c 的表現受到干擾,並引發大量的cyclin D1 (ccnd1) 的表現,同時elavl3/HuC的表現減少,並大量增加pcna 、 nestin、ascl1b及 sox3 的表現,顯示在hif2α弱化的胚胎中存活的神經先驅細胞大部分維持在細胞增生 (proliferation) 的狀態未進行細胞分化。依據這些結果推測在斑馬魚胚胎內因HIF2α弱化所造成的種種發育缺陷部分原因乃歸咎於缺少Survivin的活性所致。
Abstract Hypoxia-inducible factor (HIF) 1α and -2α and the inhibitor of apoptosis survivin represent prominent markers of many human cancers. They are also widely expressed in various embryonic tissues, including the CNS. However, little is known about their functions in embryos. Here it is demonstrated that zebrafish HIF2α protects neural progenitor cells and neural differentiation processes by up-regulating the survivin orthologues birc5a and birc5b during embryogenesis. Morpholino-mediated knockdown of hif2α reduced the transcription of birc5a and birc5b, induced p53-independent apoptosis and abrogated neural cell differentiation. Depletion of birc5a and birc5b recaptured the neural development defects that were observed in the hif2α morphants. The phenotypes induced by HIF2α depletion were largely rescued by ectopic birc5a and birc5b mRNAs, indicating that Birc5a and Birc5b act downstream of HIF2α. Knockdown of hif2α, birc5a or -5b reduced the expression of the cdk inhibitors p27/cdkn1b and p57/cdkn1c and increased ccnd1/cyclin D1 transcription in the surviving neural progenitor cells. The reduction in elavl3/HuC expression and enhanced pcna, nestin, ascl1b and sox3 expression indicate that the surviving neural progenitor cells in hif2α morphants maintain a high proliferation rate without terminally differentiating. We propose that a subset of developmental defects attributed to HIF2α depletion is due in part to the loss of survivin activity.
URI: http://ethesys.lib.ntou.edu.tw/cdrfb3/record/#G0D92360001
http://ntour.ntou.edu.tw/handle/987654321/30194
Appears in Collections:[生命科學暨生物科技學系] 博碩士論文

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