MOLECULAR GENETIC CONTROL OF OLIGODENDROCYTE DEVELOPMENT

描述（逐字摘要）：这项研究的长期目标是 了解少突胶质细胞的分子和遗传控制 规范和差异化。最近，三个 Nkx 同源盒基因 Nkx-6.1， Nkx-6.2 和 Nkx-2.2 已被鉴定为特异性表达于 腹侧脊髓中的少突胶质细胞前体细胞。此外， 这三个 Nkx 基因的表达也可以在分化过程中检测到。 或胚胎发生后期的成熟少突胶质细胞。于是，就已经 假设 Nkx 基因在控制 少突胶质细胞的规范、分化或成熟。四具体 这里提出的目标是检验这一假设并系统地 表征 Nkx 基因在少突胶质细胞控制中的功能 发展。目标 1 是表征少突胶质细胞表型 Nkx-2.2突变小鼠。目标 2 是研究 Nkx-6.2 的效果 少突胶质细胞分化的突变。目标 3 是研究 Nkx-2.2 和 Nkx-6.2 双突变体中少突胶质细胞的发育 研究它们在控制少突胶质细胞中可能的冗余作用 发展。目标4是测试Nkx-6.1、Nkx-6.2和Nkx-6.2的效果 通过过表达这些来异位表达对少突胶质细胞分化的影响 使用鸡胚胎背脊髓中的基因 有复制能力的禽逆转录病毒作为基因传递系统。测试 需要三个 Nkx 基因同时表达的可能性 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 表达在 Nkx-6.1 和 Nkx-6.2 域。因此，心室前体细胞 Nkx-2.2 和 Nkx-6.1 共表达，Nkx-6.2 也在背侧扩展 Pax-6 突变体和少突胶质细胞前体结构域可能符合 向背侧延伸。 拟议研究的结果将显着增强我们的能力 了解控制早期规范的遗传电路和 少突胶质细胞的分化，并可为设计提供理论依据 预防和治疗运动神经元的新治疗方法 和少突胶质细胞萎缩。

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.