- 學位論文
探討微核醣核酸-125b1與賈可森症候群之關聯性
Investigating the relationships between microRNA-125b1 and Jacobsen Syndrome
摘要
微核醣核酸（microRNA）為物種間高度保留之非轉譯型小核醣核酸分子，具有轉錄後調控基因表現之功能。微核醣核酸-125b（miR-125b）為微核醣核酸-125b1及微核醣核酸-125b2經轉錄後修飾產生，高度表現於大腦及神經系統。在線蟲、果蠅及斑馬魚的微核醣核酸-125b剔除模型中皆顯示於個體發育及神經系統分化扮演重要角色。賈可森症候群(Jacobsen syndrome)為罕見染色體缺失疾病，又稱為11q缺失症候群，主要於人類11號染色體長臂23.3至末端(11q23.3-qter)發生部分缺失，造成大量基因刪除，導致許多生理病徵及行為異常，包括血小板數量減少及功能異常、生長遲緩、大腦異常等問題，也常伴隨學習認知障礙、自閉症類群障礙等行為缺失，至今仍無代表性單一基因剔除動物模型模擬賈可森症候群。微核醣核酸-125b1基因位於賈可森症候群染色體缺失區域，本論文利用Mir125b1單套基因剔除小鼠(Mir125b1+/-)，分析其生理狀況及行為，評估其是否可成為賈可森症候群之動物模型。本研究發現Mir125b1+/- 10週齡小鼠體重較輕，進一步量測重要器官發現大腦重量明顯較輕，顯示Mir125b1+/-小鼠大腦及生長發育受到影響。經分析Mir125b1+/-小鼠全血無此症候群常見血小板不足病徵。在多套行為試驗中，Mir125b1+/-小鼠的活動能力、運動協調能力及社交行為無明顯異常，但有焦慮及易沮喪傾向，顯示Mir125b1+/-小鼠具有自閉症類群障礙傾向。另由於水迷津及巴恩斯迷宮試驗實驗結果互異，因此無法證實Mir125b1+/-小鼠是否具有空間記憶學習障礙。為分析Mir125b1+/-小鼠大腦與沮喪相關性，藉由量測大腦厚度發現Mir125b1+/- 18.5天胚胎及10週齡成鼠大腦皮質厚度皆較野生正常者薄。根據實驗結果，本論文證明Mir125b1+/-小鼠個體發育及大腦器官受到影響，並推估具有賈可森症候群的自閉症類群障礙表徵，可能成為此疾病代表之動物模型。
並列摘要
MicroRNAs (miRNA) are polygenetically highly conserved small non-coding RNAs which regulate gene expression post-polygenetically. MicroRNA-125b (miR-125b) is generated from miR-125b1 and miR-125b2 and highly expressed in brain and neuron. MiR-125b plays an important role in the organism development and differentiation of the neuron system evidenced by many miR-125b knockout animal models including C. elegans, Drosophila and zebrafish. Jacobsen syndrome (JS) is a rare chromosomal deletion disorder, also called 11q terminal deletion disorder. This disease is mainly caused by partial deletion of the long arm of chromosome 11 including the q23.3 to the end of 11q (11q23.3-qter) which results in multiple genes depletion and causes physiological and behavioral abnormalities such as thrombocytopenia, abnormal platelet function, growth retardation, and brain abnormality. Patients may have cognitive learning problem and autism spectrum disorder. There is no single gene knockout animal model mimicking Jacobsen syndrome until now. Since miR-125b1 gene is located in the deletion region of Jacobsen syndrome, the goal of this study is evaluating whether the Mir125b1 heterozygous knockout mice (Mir125b1+/- mice) can be an animal model of Jacobsen syndrome by analyzing the physical condition and the behavior of Mir125b1+/- mice. The weight of Mir125b1+/- 10 week-old mice were lower than their littermate controls groups. Moreover, by analyzing the weight of major organs, the brain weight of Mir125b1+/- mice were decreased compared with their control groups. These results implied the growth of the brain and weight of Mir125b1+/- mice may be affected. Although the platelet abnormality is commonly found in patients with Jacobsen syndrome, the PLT count of Mir125b1+/- mice did not show any significant difference. In multiple behavior tests, Mir125b1+/- mice showed normal mobility, motor coordinating ability, and social behavior; however, the anxiety and depression tendency of Mir125b1+/- mice were significantly increased. These results suggested that Mir125b1+/- mice might have autism spectrum disorder. On the other hand, the consequences of water maze and the barnes maze test were incompatible. It is still controversial whether Mir125b1+/- mice have the spatial learning and memorial problems. To establish the correlation of the deficit of cerebral cortex and depression in Mir125b1+/- mice, the thickness of cortical cortex in Mir125b1+/- E18.5 embryos and 10 week-old mice were measured and both were significantly thinner than their WT controls. In conclusion, my thesis proofed that Mir125b1+/- mice with reduced weight in body and brain and autism-like spectrum disorder behaviors, indicating Mir125b1+/- mice might be a potential animal model of Jacobsen syndrome.