Muscle spindle development and function in wildtype and mutant mice

肌梭是一种复杂的拉伸敏感型机械感受器，几乎存在于每一块肌肉中。它们由特殊的骨骼肌纤维组成，称为梭内纤维，在中央(赤道)区域由传入感觉轴突支配，在两极区由传出的运动神经元支配。肌梭是伸展的探测器，产生动作电位的频率与伸展的大小和速度成正比。肌梭是我们身体的主要本体感受器，为中枢神经系统提供有关我们四肢在空间中的位置和运动的信息。虽然肌梭的一般功能已经被很好地描述，但这种功能的分子基础和肌梭的病理变化大多是未知的。在这项提案中，我们希望通过具体解决两个问题来扩展我们对野生型和突变小鼠肌梭功能的分子基础的研究。我们想要通过分析骨骼肌特异缺失两种桥粒蛋白的小鼠来确定a)通过桥粒在感觉神经元和梭内纤维之间的直接分子连接所起的作用，以及b)在Friedreich共济失调的小鼠模型中研究肌梭感觉神经的退化和再生。为了解决第一个问题，我们产生了骨骼肌特异的桥粒蛋白-2和蛋白球蛋白基因敲除的小鼠，这是桥粒的两个成分，在肌梭中表达。这些小鼠的肌梭将通过电生理学、行为测试和共聚焦显微镜进行分析，以确定功能和结构的变化。同样的方法将被用于分析Friedreich共济失调的小鼠模型。这些小鼠具有感觉神经元特异性的Frataxin基因失活，这会导致肌梭感觉神经末梢的退化，随后导致运动控制和共济失调的问题。通过注射携带Frataxin基因的腺相关病毒，在症状后动物体内重新表达Frataxin，可导致感觉神经再生，改善运动控制问题和共济失调。因此，这些小鼠代表了一个很好的模型，适合于研究成人梭内纤维感觉神经的去化和再生，而不损害梭形运动控制，也不需要手术和随后的瘢痕形成。总之，这些研究将大大提高我们对肌梭功能的分子机制的理解，并可能为Friedreich共济失调患者提供潜在的治疗策略。

Muscle spindles are complex stretch-sensitive mechanoreceptors present in almost every muscle. They consist of specialized skeletal muscle fibers, called intrafusal fibers, which are innervated in the central (equatorial) region by afferent sensory axons and in both polar regions by efferent -motoneurons. Muscle spindles are stretch detectors and generate action potentials with frequencies proportional to the amount of stretch as well as to the speed of stretching. Muscle spindles are the main proprioceptors in our body and provide the CNS with information about the position and movement of our extremities in space. While the general function of muscle spindles has been rather well described, the molecular basis of this function and the pathological changes of muscle spindles are mostly unknown. In this proposal, we want to extend our studies on the molecular basis of muscle spindle function in wildtype and mutant mice by specifically addressing two questions. We want to determine a) the role of a direct molecular connection between sensory neuron and intrafusal fiber via desmosomes by analyzing mice with a skeletal muscle-specific deletion of two desmosomal proteins and b) investigate the degeneration and regeneration of the muscle spindle’s sensory innervation in a mouse model for Friedreich Ataxia. To address the first question, we have generated mice with a skeletal muscle-specific knockout of desmoglein-2 and plakoglobin, two components of desmosomes expressed in muscle spindles. Muscle spindles from these mice will be analyzed by electrophysiology, behavioral tests and confocal microscopy to determine functional and structural changes. The same methods will be used to analyze a mouse model for Friedreich Ataxia. These mice have a sensory neuron-specific inactivation of the frataxin gene, which leads to a degeneration of the sensory nerve terminal in muscle spindles and subsequently to problems in motor control and ataxia. Reexpression of frataxin in post-symptomatic animals by injection of an adeno-associated virus harboring the frataxin cDNA results in a regeneration of the sensory innervation and an amelioration of the motor control problems and the ataxia. Thus, these mice represent a model well suited to investigate de- and regeneration of sensory innervation of adult intrafusal fibers without compromised fusimotor control and without surgery and subsequent scar formation. Together these studies will considerably enhance our understanding of the molecular mechanisms responsible for muscle spindle function and might lead to potential therapeutic strategies for patients with Friedreich Ataxia.