Retinoids and the specification of spinal motor neurons
类维生素A和脊髓运动神经元的规范
基本信息
- 批准号:6667904
- 负责人:
- 金额:$ 34.95万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2003
- 资助国家:美国
- 起止时间:2003-06-01 至 2007-05-31
- 项目状态:已结题
- 来源:
- 关键词:cell communication molecule cell population study chick embryo developmental genetics developmental neurobiology electroporation embryogenesis gene expression gene targeting genetically modified animals laboratory mouse mesoderm motor neurons neural plate /tube neurogenesis retinoids spinal nerves ventral column vertebrate embryology
项目摘要
The coordinated generation of specialized groups of spinal motor neurons during development of the central nervous system is essential for the assembly of functional neural circuits. Analysis to date hasfocused on the role of the signaling molecule shh in motor neuron specification however increasing evidencesuggests that other inductive molecules may play pivotal roles in their development. The dynamicspatiotemporal expression of RALDH2, the major synthetic enzyme for retinoic acid suggests that retinoidsignaling is required at defined stages in the sequential development of motor neurons. However, loss offunction studies have not been informative due to the early lethality of RALDH2 null embryos. This proposalaims to test the hypothesis that retinoids are required at specific stages of motor neuron development usinggenetic strategies in the mouse to bypass the early lethality of RALDH2 mutants. Tissue specific knockouts
of RALDH2 will be constructed and analyzed to first assess the contribution of paraxial mesoderm derived retinoids to motor neuron generation and column induction and second, to determine if motor neuron derived retinoid signaling is necessary for motor column, motor division and motor pool determination. Finally, four prospective target genes for RALDH2 have been isolated using differential screening approaches and experiments outlined here will focus on functional analyses to determine the potential role of two of these genes in motor neuron specification. Taken together, these experiments aim to define the contribution of retinoic acid signaling to motor neuron development with the ultimate aim of assembling a molecular pathway of retinoid dependent events required for their specification during embryogenesis. Understanding the processes by which motor neuron specification occurs may provide insight into the basis of motor neuron degenerative diseases such as amyotrophic lateral sclerosis or the spinal muscular atrophies. This in turn may lead to the design of innovative treatments for these diseases in the future which may incorporate the use of stem cell technology.
在中枢神经系统发育过程中,脊髓运动神经元组的协调生成对功能神经回路的组装是必不可少的。到目前为止,分析主要集中在信号分子shh在运动神经元规范中的作用,然而越来越多的证据表明,其他诱导分子可能在它们的发育中发挥关键作用。维甲酸的主要合成酶RALDH2的动态时空表达表明,在运动神经元的连续发育的特定阶段,维甲酸信号是必需的。然而,由于RALDH2缺失胚胎的早期致死性,功能丧失的研究并不是很有价值。这项提议旨在通过在小鼠中使用遗传策略绕过RALDH2突变体的早期致死性来检验这一假设,即在运动神经元发育的特定阶段需要维甲酸。组织特异性基因敲除
将构建和分析RALDH2,以首先评估近轴中胚层衍生的视黄醇对运动神经元的产生和柱状诱导的贡献,其次,确定运动神经元衍生的视黄醇信号对于运动柱、运动分裂和运动池的确定是否必要。最后,使用差异筛选方法分离了RALDH2的四个潜在靶基因,这里概述的实验将集中在功能分析上,以确定其中两个基因在运动神经元指定中的潜在作用。综上所述,这些实验旨在确定维甲酸信号对运动神经元发育的贡献,最终目的是组装一条在胚胎发育过程中指定它们所需的维甲酸依赖事件的分子途径。了解运动神经元指定发生的过程可能有助于深入了解运动神经元退行性疾病的基础,如肌萎缩侧索硬化症或脊髓性肌萎缩。这反过来可能导致未来针对这些疾病的创新治疗方法的设计,其中可能包括干细胞技术的使用。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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SHANTHINI SOCKANATHAN其他文献
SHANTHINI SOCKANATHAN的其他文献
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{{ truncateString('SHANTHINI SOCKANATHAN', 18)}}的其他基金
Roles for activity-dependent microvesicles in neuronal health and disease
活性依赖性微泡在神经元健康和疾病中的作用
- 批准号:
10426437 - 财政年份:2022
- 资助金额:
$ 34.95万 - 项目类别:
Molecular mechanisms of motor neuron development
运动神经元发育的分子机制
- 批准号:
7848069 - 财政年份:2003
- 资助金额:
$ 34.95万 - 项目类别:
Retinoids and the specification of spinal motor neurons
类维生素A和脊髓运动神经元的规范
- 批准号:
7076241 - 财政年份:2003
- 资助金额:
$ 34.95万 - 项目类别:
Molecular mechanisms of motor neuron development
运动神经元发育的分子机制
- 批准号:
7365495 - 财政年份:2003
- 资助金额:
$ 34.95万 - 项目类别:
Molecular Mechanisms of Cellular Differentiation in the Nervous System
神经系统细胞分化的分子机制
- 批准号:
8501897 - 财政年份:2003
- 资助金额:
$ 34.95万 - 项目类别:
Molecular Mechanisms of Cellular Differentiation in the Nervous System
神经系统细胞分化的分子机制
- 批准号:
8650923 - 财政年份:2003
- 资助金额:
$ 34.95万 - 项目类别:
Molecular Mechanisms of Cellular Differentiation in the Nervous System
神经系统细胞分化的分子机制
- 批准号:
9020270 - 财政年份:2003
- 资助金额:
$ 34.95万 - 项目类别: