探討早幼粒細胞白血病鋅指蛋白(Plzf)對腦部發育的作用

Characterization of the Functional Role of Promyelocytic Leukemia Zinc Finger Protein (Plzf) in Brain Development

林心荃(Hsin-Chuan Lin)

指導教授 ： 張文昌

共同指導教授 ： 李宜釗(Yi-Chao Lee)

臺北醫學大學/醫學院/醫學科學研究所/博士(2019年)

摘要

早幼粒細胞白血病鋅指蛋白(Plzf)是一個轉錄調控因子，在胚胎發育過程中參與在許多重要的生物途徑，已知可以維持神經幹細胞並且阻止神經幹細胞分化成神經元。然而，究竟Plzf對於腦部的結構及功能會有什麼影響至今仍不清楚。在這個研究中，我們發現缺少Plzf會造成發育早期前腦腦室區進行有絲分裂的細胞數目降低，進而影響深層皮質神經細胞的生成，最終導致小鼠的大腦皮質過小，同時也影響認知記憶的功能。利用微陣列、即時定量反轉錄聚合酶連鎖反應以及流式細胞進一步分析顯示缺少了Plzf會造成小鼠胚胎腦部組織中原神經基因Mash1的表現失調。我們的結果也顯示在胚胎發育時期第9.5天可以在腦部表現Pax6蛋白的細胞中偵測到Plzf的表現，且Plzf在端腦的表現會在大腦皮質要進行神經生成前完全消失，利用P19胚胎癌細胞作為細胞模型，我們進一步發現轉錄因子E2f可以在類神經幹細胞形成時誘導Plzf的表現。我們的研究結果發現Plzf表現異常會造成小鼠腦部的結構與功能的異常，同時也進一步提供了Plzf在腦發育過程中可能受到的調控機轉。

關鍵字

早幼粒細胞白血病鋅指蛋白 ； 腦部發育

並列摘要

Promyelocytic leukemia zinc finger (Plzf), a transcriptional regulator involved in a lot of important biological processes during development, has been implied to maintain neural stem cells and inhibit their differentiation into neurons. However, the effects of Plzf on brain structures and functions are still not clarified. In this study, we found that loss of Plzf resulted in a smaller cerebral cortex with a decrease in the number of Tbr1+ deep layer neurons due to a decrease of mitotic cell number in the ventricular zone of forebrain at early developmental stages. We also observed an impairment of recognition memory in Plzf-deficient mice. Microarray, qRT-PCR, and flow cytometry analysis identified that loss of Plzf resulted in dysregulation ofMash1 proneural gene expression. We observed that Plzf expression was detected as early as embryonic day (E) 9.5 in Pax6+ cells in the mouse brain, and was completely disappeared in telencephalon before the initiation of cortical neurogenesis. Moreover, using P19 embryonal carcinoma cells as a model, we found that E2f1 functions as an important transcription factor to regulate the induction of Plzf in the neural stem- like cells. Our results show that loss of Plzf results in structural and functional abnormalities of the brain in mice and also provide insight into expression regulation of Plzf during brain development.

並列關鍵字

Plzf ； Brain Development

參考文獻

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