Functions of HIF Gene Regulatory Network in Zebrafish Neural Development

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簡歷

基本資料

Project title

Code/計畫編號

NSC102-2313-B019-010-MY3

Translated Name/計畫中文名

HIF基因調控網路在斑馬魚神經發育過程中的角色

Project Coordinator/計畫主持人

Chin-Hwa Hu

Funding Organization/主管機關

National Science and Technology Council

Co-Investigator(s)/共同執行人

鄒文雄
白敦文

Department/Unit

Department of Bioscience and Biotechnology

Website

https://www.grb.gov.tw/search/planDetail?id=3083875

Year

2013

Start date/計畫起

01-08-2013

Expected Completion/計畫迄

01-07-2014

Co-Investigator(s)

Wen-Shyong Tzou

Bugetid/研究經費

1420千元

ResearchField/研究領域

生物技術(理)
生物科學

在神經細胞分化過程中，Survivin負責保護細胞，促進中樞神經先驅細胞分化的進行。在斑馬魚胚胎中，HIF2α與其下游目標基因Survivin/Birc5a大量表現在中樞神經中，抑制任一基因的表現均會引起神經細胞的凋亡，而存活的神經先驅細胞則無法順利脫離細胞週期，進行細胞分化作用，但是其詳細的機制並不清楚。在本計畫中，我們發現在斑馬魚的神經發育時期，除了HIF2α與Survivin外，Epo亦在中樞神經區域大量表現，抑制其表現會使得神經細胞的分化受到嚴重的影響，並且誘發大量的神經細胞凋亡，顯示Epo對於神經的發育亦扮演重要的功能。這項結果與老鼠胚胎內所發現的抑制EPO訊息系統會造成腦神經細胞的凋亡，並且影響神經細胞的分化作用相吻合。經過進一步的實驗，發現Survivin與Epo的表現有相互的關聯性，抑制其中任一基因的表現均會降低另一基因的表現，顯示在胚胎的發育過程中，Survivin與Epo間存在密切的相互作用，共同控制神經的發育。在epo基因的調控方面，我們發現抑制HIF2α表現會造成胚胎神經細胞內epo的表現明顯降低，顯示HIF2α可能調控了epo的表現。除了參與神經細胞的分化之外，神經細胞所表現的EPO亦調控紅血球細胞的生成。我們推測在胚胎的神經幹細胞內hif2α、epo與birc5a三者間形成一個網路系統，共同參與神經細胞分化與紅血球的生成。我們的實驗結果對於Survivin及EPO在胚胎發育過程中的作用機制提供了重要的線索。實驗結果顯示在中樞神經先驅細胞內，EPO相關訊息系統可能是透過Survivin的協力作用，達到保護細胞並促進神經細胞分化的目的。最近的研究發現位於粒線體上的Survivin會抑制粒線體氧化磷酸化反應，促進粒線體分裂，降低活性氧累積，並讓細胞代謝轉向有氧糖解作用，以利於神經細胞分化過程的進行。我們目前正在進一步探討Survivin、EPO間的基因網路以及瞭解神經細胞糖解代謝和神經發育間的關聯性。 HIF2α protects neural progenitor cells and neural differentiation processes by up-regulating the survivin orthologues birc5a during embryogenesis. Depletion of hif2α or birc5a induced apoptosis and abrogated neural cell differentiation. The surviving neuronal progenitor cells remained in the cell cycle. The phenotypes induced by HIF2α depletion were largely rescued by ectopic birc5a mRNA, indicating that Birc5a acts downstream of HIF2α. Here we found that erythropoietin (epo) expression is coordinately regulated with birc5a by HIF2α in CNS neural progenitor cells. Depletion of EPO induced significant apoptosis and abrogated CNS differentiation, indicating EPO plays critical functions in neuronal differentiation. It is consistent with previous observations that interfering EPO signaling resulted in apoptosis and abrogated CNS neural differentiation. It was noted that a coordinative regulations existed between birc5a and epo transcription. Depletion either gene resulted in reduction of another gene transcription. It appears that the neuronal differentiation is controlled by a close interactions between Survivin and EPO. Chromatin immunoprecipitation has revealed a direct binding of HIF2α in the upstream region of epo gene in the developing embryos. EPO also promotes erythropoiesis in the developing embryos. We expect that the CNS differentiation and erythropoiesis is coordinately regulated by an interacting network between hif2α, birc5a, and epo. Our results may explain the functions of Survivin and EPO in the developing embryos. Recent studies found that the mitochondrial Survivin plays important function to block oxidative phosphorylation and promote mitochondrial fission, which prevents ROS accumulation and leads to aerobic glycolysis. Currently we are studying the mechanism of birc5a and epo interactions and their functions in neuronal metabolism and neuronal differentiation.

Keyword(s)

斑馬魚胚胎
低氧誘發蛋白HIF2α
抗凋亡蛋白Birc5a/-5b
神經攜氧蛋白Ngb/Cygb
神經細胞基因調控蛋白NeuroD
神經發育
基因轉錄體
基因默化
HIF2α
Birc5a/-5b
NeuroD
neuroglobin
cytoglobin
neural development
transcriptome
gene silencing
zebrafish

DSpace CRIS

Functions of HIF Gene Regulatory Network in Zebrafish Neural Development

基本資料

Description