Molecular profiling of gamma motor neuron development

描述(申请人提供)：伽马运动神经元(g-MN)是一个功能和解剖学上不同的神经元亚类，在大多数运动池中大量发现。这些“梭形马达”神经元专门支配肌梭内的纤维，并组成一个平行的运动系统，独立于梭外肌肉激活肌梭纤维。控制g-MN的指定和分化的机制尚不清楚，也没有识别出特定的标记物来区分发育早期的g和运动神经元。我们已经发现G融合运动神经元选择性地依赖于靶肌梭来源的GDNF，最近的一项研究报道在胚胎发育过程中融合运动神经元也选择性地依赖于GDNF信号。利用这一营养需求作为功能标记，我们建议使用突变小鼠对g-MN中选择性表达的基因进行差异筛选，其中g-MN前体在缺乏GDNF信号的情况下选择性丢失。我们还将在小鼠胚胎干细胞来源的运动神经元培养中利用g-MNS的这一特殊特性来描述g-MNS在体外的基因表达模式。最后，我们将使用我们以前的工作中建立的分子和大小标准来选择性地分离出生后g-MN用于分子分析。确定g-MNS在不同发育阶段特异表达的基因，将使分子遗传学方法能够研究梭形马达系统的形成和功能，包括它在正常运动行为和运动控制障碍中的作用。 公共卫生相关性：伽马运动神经元通过控制骨骼肌中伸展感受器的敏感性来调节从外周到中枢神经系统的感觉反馈。它们的功能对运动控制和我们感知肢体在太空中的位置至关重要。这项研究将提供伽马运动神经元的分子图谱，为未来研究这一运动系统在健康和疾病中的作用铺平道路。

DESCRIPTION (provided by applicant): Gamma motor neurons (g-MNs) are a functionally and anatomically distinct subclass of neurons found in large number in most motor pools. These "fusimotor" neurons exclusively innervate the intrafusal fibers of the muscle spindle and comprise a parallel motor system that activates muscle spindle fibers independently of extrafusal muscle. The mechanisms that control the specification and differentiation of g-MNs are unknown, and no specific markers have been identified to distinguish g from a motor neurons in early development. We have found that g fusimotor neurons are selectively dependent on target muscle spindle-derived GDNF, and a recent study reports that fusimotor neurons are also selectively dependent on GDNF signaling in embryogenesis. Using this trophic requirement as a functional marker, we propose to perform a differential screen for genes selectively expressed in g-MNs using a mutant mouse in which g- MN precursors are selectively lost in the absence of GDNF signaling. We will also exploit this specific property of g-MNs in cultures of mouse embryonic stem cell-derived motor neurons to profile the pattern of gene expression in g-MNs in vitro. Finally, we will use molecular and size criteria established in our previous work to selectively isolate postnatal g-MNs for molecular analysis. The identification of genes specifically expressed in g-MNs at different stages of development will make possible a molecular genetic approach to study the formation and function of the fusimotor system, including its role in normal motor behaviors and disorders of motor control. PUBLIC HEALTH RELEVANCE: Gamma motor neurons regulate sensory feedback to the central nervous system from the periphery by controlling the sensitivity of stretch receptors in skeletal muscle. Their function is critical for motor control and for our perception of where our limbs are in space. This study will provide a molecular profile of gamma motor neurons, opening the way to future study of this motor system in health and disease.