Motor neuron diversity: markers, regulatory mechanisms, and functional relevance.

描述（由申请人提供）：概述破坏性运动神经元疾病肌萎缩性侧索硬化症和脊髓性肌萎缩症导致运动神经元亚群的差异性变性。人类拥有数百种运动神经元亚型，这些亚型在形态、功能特性、基因表达模式、分子特征和连接性方面不同。关于如何识别/定义终末运动神经元亚型或为什么有些亚型比其他亚型更容易受到疾病过程的影响，人们知之甚少。 本研究的目的是在C语言中使用一种独特的自下而上的方法。elegans来确定产生运动神经元亚型的定义因子和调节机制，并了解运动神经元亚型多样性的功能重要性。这将通过研究一个胆碱能运动神经元亚型在C。elegans腹神经索，AS运动神经元，以及unc-55在指定AS亚型命运中的潜在作用。利用C. elegans和基因调控的分析，将鉴定分子上相互定义亚型的新因子，并确定unc-55在调节这些因子中的作用。接下来，候选的方法和无偏的正向遗传筛选将定义在AS运动神经元中unc-55的调节，利用C.优雅最后，AS运动神经元的功能重要性将通过结合光学消融、光学神经元活动监测和AS运动神经元的光遗传学操纵与自由行为的蠕虫中的先进蠕虫跟踪和成像来定义。 这项提案将定义AS运动神经元的规格和功能，但也广泛地解决产生运动神经元亚型的机制。揭示识别、调节和维持运动神经元亚型的分子机制与运动神经元变性特别相关，并且可以为运动神经元相关疾病的发病机制、疾病诊断和治疗提供新的靶标。

DESCRIPTION (provided by applicant): Summary The devastating motor neuron diseases Amyotrophic Lateral Sclerosis and Spinal Muscular Atrophy cause differential degeneration of subsets of motor neurons. Humans possess hundreds of subtypes of motor neurons that differ in morphology, functional properties, gene expression patterns, molecular signatures, and connectivity. Little is known about how to identify/define terminal motor neuron subtypes or why some are more susceptible to disease processes than others. The goal of this research proposal is use a unique 'bottom-up' approach in C. elegans to identify defining factors and regulatory mechanisms for generating motor neuron subtypes and to understand the functional importance of motor neuron subtype diversity. This will be achieved by studying one cholinergic motor neuron subtype in the C. elegans ventral nerve cord, the AS motor neurons, and the potential role for unc-55 in specifying AS subtype fate. Using C. elegans and analysis of gene regulation, novel factors that molecularly define subtypes from one another will be identified, and the role for unc-55 in regulating these factors will be determined. Next, a candidate approach and an unbiased forward genetic screen will define the regulation of unc-55 in AS motor neurons, utilizing both manual and automated genetic screening techniques in C. elegans. Lastly, the functional importance of the AS motor neurons will be defined by combining optical ablation, optical neuronal activity monitoring, and optogenetic manipulation of AS motor neurons with advanced worm tracking and imaging in freely behaving worms. This proposal will define the specification and function of AS motor neurons, but also broadly address the mechanisms for generating motor neuron subtypes. Unraveling the molecular mechanisms that identify, regulate, and maintain motor neuron subtypes are particularly relevant to motor neuron degeneration, and may provide novel targets for pathogenesis, disease diagnosis, and therapeutics for motor neuron related diseases.