Muscle spindle development and function in wildtype and mutant mice

野生型和突变型小鼠的肌梭发育和功能

• 批准号: 329845490
• 负责人: Professor Dr. Stephan Kröger
• 金额: --
• 依托单位: Biomedizinisches Centrum München (BMC)
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/329845490?language=en
• 关键词: Muscle; spindle; development; function; wildtype

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.

肌梭是复杂的牵张敏感性机械感受器，几乎存在于每一块肌肉中。它们由称为梭内纤维的特化骨骼肌纤维组成，其在中央（赤道）区域由传入感觉轴突支配，在两极区域由传出运动神经元支配。肌梭是拉伸检测器，并产生频率与拉伸量和拉伸速度成比例的动作电位。肌梭是我们身体中的主要本体感受器，并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被相当好地描述，但这种功能的分子基础和肌梭的病理变化大多是未知的。在这个提议中，我们希望通过具体解决两个问题来扩展我们在野生型和突变小鼠中肌梭功能的分子基础上的研究。我们想确定a）通过分析具有两种桥粒蛋白的骨骼肌特异性缺失的小鼠，感觉神经元和梭内纤维之间通过桥粒的直接分子连接的作用，和B）研究弗里德赖希共济失调小鼠模型中肌梭感觉神经支配的变性和再生。为了解决第一个问题，我们产生了骨骼肌特异性敲除桥粒芯糖蛋白-2和斑珠蛋白的小鼠，这两种组分是肌梭中表达的桥粒。将通过电生理学、行为测试和共聚焦显微镜分析这些小鼠的肌梭，以确定功能和结构变化。将使用相同的方法分析Friedreich共济失调的小鼠模型。这些小鼠具有共济失调蛋白基因的感觉神经元特异性失活，这导致肌梭中感觉神经末梢的变性，随后导致运动控制和共济失调的问题。通过注射携带共济失调蛋白cDNA的腺相关病毒在症状后动物中重新表达共济失调蛋白，导致感觉神经支配的再生和运动控制问题和共济失调的改善。因此，这些小鼠代表了一种非常适合研究成人梭内纤维感觉神经支配的去和再生的模型，而不损害梭运动控制，也不需要手术和随后的瘢痕形成。这些研究将大大提高我们对肌梭功能的分子机制的理解，并可能为弗里德赖希共济失调患者提供潜在的治疗策略。