GENE AND TRANSGENE REGULATION IN THE DEVELOPING MOUSE

发育中小鼠的基因和转基因调控

• 批准号: 3842240
• 负责人: H WESTPHAL
• 金额: --
• 依托单位: EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3842240
• 关键词: Gaucher's disease; T cell receptor; antigen receptors; cell differentiation; cell line; developmental genetics; disease /disorder model; embryonic stem cell; gene expression; genetic regulation; genetically modified animals; growth /development; hypogonadism; laboratory mouse; lens; oncogenes; phosphoprotein phosphatase; transfection; tumor suppressor genes

Lens oncogenesis and differentiation. A dormant oncogene has been activated in the transgenic mouse via the prokaryotic, site-specific recombinase CRE. The onset of oncogene expression has been directed to coincide with specific stages of lens development. Lens fiber cells can thus be immortalized at distinct stages along their pathway to terminal differentiation. Expression of nm23 during mouse development. The expression of nm23 has been described as a marker of non-metastatic growth properties of certain rodent and human tumors. During mouse development, we detect high levels of the nm23 gene during organogenesis. Expression appears confined to epithelial tissues, and is especially prominent between the onset and the terminal phase of differentiation. This expression pattern correlates well with the inverse relationship between nm23 expression and invasiveness observed in tumors of epithelial origin. Role of the T-cell receptor (TCR) zeta chain in thymocyte development. The TCR-zeta chain is an essential subunit of both the T-cell antigen receptor complex and certain Fc receptors. In both contexts, zeta in required for receptor surface expression and ligand-mediated signal transduction. To examine the role of TCR-zeta in T-cell ontogeny, transgenic mice expressing high levels of full-length or mutated forms of the zeta chain have been generated and analyzed. The results suggest that 1) zeta-mediated signalling pathways control early thymocyte developmental events such as TCR alpha and beta gene rearrangement, and 2) surface expression of TCR complexes during development is controlled by the level of intracellular zeta chain. Animal modal of Gaucher's disease from targeted disruption of the mouse glucocerebrosidase (GC) gene. In a large collaborative experiment, we generated a null allele of GC in murine embryonic stem cells by inserting a neomycin resistance gene in the chromosomal target gene. Mutant embryonic stem cells were injected into normal blastocysts, and a chimeric germ line mutation was obtained. Mice homozygous for the GC mutation have less than 4% of normal GC activity, die shortly after birth and show a lysosomal storage disorder that resembles that of Gaucher patients. The animals will therefore be valuable for investigating the pathogenesis of the human disease and for evaluating therapeutic approaches.

晶状体的肿瘤发生和分化。 休眠的癌基因已通过转基因小鼠激活 原核，特异性重组酶CRE。癌基因的发作 表达已被指示与特定镜头的特定阶段一致 发展。 透镜纤维细胞因此可以在不同的 沿其终端分化的途径阶段。 NM23在小鼠发育过程中的表达。 NM23的表达已被描述为非中性的标记 某些啮齿动物和人类肿瘤的生长特性。 在鼠标期间 开发，我们检测到高水平的NM23基因 器官发生。 表达似乎仅限于上皮组织，并且 在发作和终端相之间特别突出 分化。 此表达模式与 观察到NM23表达与侵入性之间的逆关系 在上皮起源的肿瘤中。 T细胞受体（TCR）Zeta链在胸腺细胞发育中的作用。 TCR-Zeta链是两种T细胞抗原的必不可少的亚基 受体复合物和某些FC受体。 在这两种情况下，zeta in 受体表面表达和配体介导的信号所需 转导。 为了检查TCR-Zeta在T细胞个体发育中的作用， 表达高水平全长或突变形式的转基因小鼠 已经生成和分析了Zeta链的。 结果表明 1）Zeta介导的信号通路控制早期胸腺细胞 TCR Alpha和Beta基因重排等发展事件，以及 2）在发育过程中控制TCR复合物的表面表达 按细胞内Zeta链的水平。 靶向小鼠的动物模态因小鼠的靶向破坏 葡萄糖脑溴糖苷酶（GC）基因。 在一个大型协作实验中，我们在GC中产生了无效的GC等位基因 鼠胚胎干细胞通过将新霉素抗性基因插入 染色体靶基因。 注射突变的胚胎干细胞 进入正常的胚泡，并获得了嵌合种系突变。 纯合的GC突变的小鼠少于正常GC的4％ 活动，出生后不久死亡并显示出溶酶体储存障碍 这类似于Gaucher患者。 因此，动物将是 对于调查人类疾病的发病机理和用于 评估治疗方法。