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
• 负责人: SHANTHINI SOCKANATHAN
• 金额: $ 34.13万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/7076241
• 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

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.

中枢神经系统发育期间脊髓运动神经元特化群的协调生成对于功能神经回路的组装至关重要。迄今为止的分析主要集中在信号分子shh在运动神经元特化中的作用，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起关键作用。视黄酸的主要合成酶RALDH 2的动态时空表达表明，在运动神经元连续发育的特定阶段需要视黄酸信号。然而，由于RALDH 2无效胚胎的早期致死性，功能丧失研究没有提供信息。该提议旨在验证这一假设，即在小鼠运动神经元发育的特定阶段，需要使用遗传策略来绕过RALDH 2突变体的早期致死性。组织特异性敲除 将构建并分析RALDH 2的信号传导，以首先评估近轴中胚层衍生的类视色素对运动神经元产生和柱诱导的贡献，其次确定运动神经元衍生的类视色素信号传导是否是运动柱、运动分裂和运动池确定所必需的。最后，四个前瞻性的靶基因RALDH 2已被分离使用差分筛选方法和实验概述这里将集中在功能分析，以确定这些基因中的两个在运动神经元的规范的潜在作用。总之，这些实验旨在确定视黄酸信号传导对运动神经元发育的贡献，最终目的是组装胚胎发生期间其规格所需的视黄酸依赖性事件的分子途径。了解运动神经元特化发生的过程可以提供对运动神经元退行性疾病（如肌萎缩性侧索硬化症或脊髓性肌肉萎缩症）的基础的深入了解。这反过来又可能导致未来为这些疾病设计创新的治疗方法，其中可能包括使用干细胞技术。