| 题名 | Floped参与维持小鼠胚胎干细胞遗传物质稳定性的研究 |
| 作者 | 寸益贤 |
| 学位类别 | 硕士 |
| 答辩日期 | 2013-05 |
| 授予单位 | 中国科学院研究生院 |
| 授予地点 | 北京 |
| 导师 | 郑萍 |
| 关键词 | Floped基因 小鼠胚胎干细胞 遗传物质稳定性 DNA损伤 |
| 其他题名 | Floped, an embryonic stem cell (ESC)-specific gene, is required for maintaining the genomic stability of mouse |
| 学位专业 | 细胞生物学 |
| 中文摘要 | Floped（Factor located in oocytes permitting embryonic development，official symbol Ooep），是小鼠卵母细胞和胚胎干细胞中高丰度且特异性表达的基因。Floped基因敲除后雌鼠不育，表现为Floped缺失的卵细胞受精后胚胎发育停滞在2-细胞阶段，提示Floped在卵细胞及早期胚胎发育中具重要功能。但Floped在胚胎干细胞及着床后早期胚胎发育过程中的作用尚缺乏研究。本工作将详细研究Floped基因在小鼠胚胎干细胞中的功能及可能机制。通过建立Floped敲除的小鼠胚胎干细胞系，我们发现Floped参与维持小鼠胚胎干细胞遗传物质的稳定性。Floped缺失引起小鼠胚胎干细胞染色体分离异常，染色体粘连，断裂，出现微核和非整倍体，致瘤性增加。进一步研究发现，Floped可参与调控小鼠胚胎干细胞的DNA损伤反应。Floped缺失使DNA损伤反应信号传导不能有效维持，且使胚胎干细胞在受到DNA损伤后更易发生分化，对DNA损伤的敏感性显著增高。Filia基因也是调控小鼠胚胎干细胞遗传物质稳定性的另一重要因子。已证明卵细胞中Floped蛋白和Filia蛋白能相互结合形成复合体。小鼠胚胎干细胞Floped和Filia是否也能相互结合，并在功能上具有相关性还需要更进一步研究。 |
| 英文摘要 | Floped （Factor located in oocytes permitting embryonic development，official symbol Ooep）,is abundantly and specifically expressed in growing oocytes as well as embryonic stem (ES) cells in mice. Depletion of maternal Floped protein from oocytes led to embryo arrest at two-cell stage, suggesting that Floped played essential yet unknown functions in early embryonic development. Although the transcripts of Floped are abundant in ES cells, it remains elusive whether Floped also plays crucial roles in these pluripotent stem cells. In this study, we investigated in detail the functions and possible mechanism of Floped in mouse ES cells. To this end, we established several lines of Floped-/- ES cells and carefully investigated the possible phenotypes. Depletion of Floped from ES cells did not cause visible or gross abnormalities in ES cells. However, ES cells without Floped displayed striking genomic instability as evidenced by the high incidences of aberrant chromosome segregation, micronucleus formation, chromosome break, and aneuploidy which in consequence led to the tumorigenic transformation of ES cells. Thus, Floped played critical roles in ensuring genomic stability of mouse ES cells. Further studies revealed that Floped was required for regulating DNA damage response. Floped depletion impaired the efficient activation of key signaling kinases ATM and Chk2 which in turn could compromise the damage response of cell cycle checkpoints. Furthermore, depletion of Floped speed up the differentiation step of mouse ES cells in response to DNA damage, leading to the elevated DNA damage sensitivity. Recently, our laboratory identidifed another important gene Filia involving in the maintenance of genomic integrity of mouse ES cells. Previous studies on growing mouse oocytes showed that Floped and Filia interacted with each other and functioned in a large protein complex. Whether these two proteins can have physical or functional interplays awaits further elucidation. |
| 语种 | 中文 |
| 公开日期 | 2013-05-23 |
| 内容类型 | 学位论文 |
| 源URL | [http://159.226.149.42:8088/handle/152453/7435]  |
| 专题 | 昆明动物研究所_哺乳动物胚胎发育 |
| 推荐引用方式 GB/T 7714 | 寸益贤. Floped参与维持小鼠胚胎干细胞遗传物质稳定性的研究[D]. 北京. 中国科学院研究生院. 2013. |
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