MOLECULAR GENETIC CONTROL OF OLIGODENDROCYTE DEVELOPMENT

少突胶质细胞发育的分子遗传控制

• 批准号: 6531082
• 负责人: Mengsheng Qiu
• 金额: $ 20.03万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-01 至 2004-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6531082
• 关键词: Retroviridae; brain; cell differentiation; cell growth regulation; chick embryo; developmental genetics; developmental neurobiology; embryo /fetus cell /tissue; gene expression; gene induction /repression; gene mutation; homeobox genes; laboratory mouse; molecular genetics; mutant; neurogenesis; oligodendroglia; phenotype; spinal cord; transfection /expression vector

DESCRIPTION (Abstract verbatim): The long-term goal of this study is to understand the molecular and genetic control of oligodendrocyte specification and differentiation. Recently, three Nkx homeobox genes, Nkx-6.1, Nkx-6.2 and Nkx-2.2, have been identified that are specifically expressed in the oligodendrocyte precursor cells in the ventral spinal cord. In addition, expression of these three Nkx genes can also be detected in the differentiating or mature oligodendrocytes at late stages of embryogenesis. Thus, it has been hypothesized that the Nkx genes play important roles in controlling the specification, differentiation or maturation of oligodendrocytes. Four specific aims are proposed here to test this hypothesis and to systematically characterize the function of the Nkx genes in the control of oligodendrocyte development. Aim 1 is to characterize the oligodendrocyte phenotypes in the Nkx-2.2 mutant mice. Aim 2 is to investigate the effects of the Nkx-6.2 mutation on oligodendrocyte differentiation. Aim 3 is to study the oligodendrocyte development in the Nkx-2.2 and Nkx-6.2 double mutants to investigate their possible redundant role in controlling the oligodendrocyte development. Aim 4 is to test the effects of Nkx-6.1, Nkx-6.2 and Nkx-6.2 ectopic expression on oligodendrocyte differentiation by overexpressing these genes in the dorsal spinal cord of chicken embryos using the replication-competent avian retrovirus as a gene delivery system. To test the possibility that simultaneous expression of three Nkx genes is required for oligodendrocyte induction, we will study the oligodendrocyte development in the Pax-6 mutants, in which the Nkx-2.2 expression is dorsally expanded within the Nkx-6.1+ and Nkx-6.2+ domain. Thus, the ventricular precursor cells coexpressing Nkx-2.2 and Nkx-6.1, Nkx-6.2 is also dorsally expanded in the Pax-6 mutants and oligodendrocyte precursor domain might be according extended dorsally. Results derived from the proposed studies will significantly enhance our understanding of the genetic circuitry governing the early specification and differentiation of oligodendrocytes, and may provide theoretic basis for design of novel therapeutic approaches for prevention and treatment of motor neuron and oligodendrocyte atrophies.

描述（逐字摘要）：本研究的长期目标是 了解少突胶质细胞的分子和遗传控制 规格和差异化。最近，三个Nkx同源盒基因，Nkx-6.1， Nkx-6.2和Nkx-2.2，已被鉴定为在人乳腺癌中特异性表达。 脊髓腹侧的少突胶质前体细胞。此外，本发明还提供了一种方法， 这三种Nkx基因的表达也可以在分化型中检测到。 或胚胎发育后期的成熟少突胶质细胞。因此， 假设Nkx基因在控制 少突胶质细胞的特化、分化或成熟。四个具体 目的是在这里提出来测试这一假设，并系统地 表征Nkx基因在少突胶质细胞控制中的功能 发展目的1是描述脑胶质细胞中少突胶质细胞的表型， Nkx-2.2突变小鼠。目的2是研究Nkx-6.2的作用 突变对少突胶质细胞分化的影响目标3是研究 Nkx-2.2和Nkx-6.2双突变体中的少突胶质细胞发育， 研究它们在控制少突胶质细胞中可能的多余作用 发展目的4是测试Nkx-6.1、Nkx-6.2和Nkx-6.2的作用 异位表达对少突胶质细胞分化的影响 基因在鸡胚胎脊髓背侧使用 复制能力的禽逆转录病毒作为基因递送系统。测试 可能需要同时表达三个Nkx基因， 少突胶质细胞诱导，我们将研究少突胶质细胞的发育， Pax-6突变体，其中Nkx-2.2的表达在Pax-6突变体中背侧扩增。 Nkx-6.1+和Nkx-6.2+结构域。因此，心室前体细胞 共表达Nkx-2.2和Nkx-6.1，Nkx-6.2也在Nkx-2.2和Nkx-6.1中背侧扩增。 Pax-6突变体和少突胶质细胞前体结构域可能与 背侧延伸。 拟议研究的结果将大大提高我们的 对控制早期规范的遗传电路的理解， 少突胶质细胞的分化，为设计提供理论依据 预防和治疗运动神经元损伤的新治疗方法 和少突胶质细胞萎缩。