Egr3-Dependent Muscle Spindle Stretch Receptor Intrafusal Muscle Fiber Differentiation and Fusimotor Innervation Homeostasis
Egr3-Dependent Muscle Spindle Stretch Receptor Intrafusal Muscle Fiber Differentiation and Fusimotor Innervation Homeostasis
复制标题
DOI：
10.1523/jneurosci.0241-15.2015
复制
发表时间：
2015-04-08
影响因子：
5.3
通讯作者：
Tourtellotte, Warren G.
中科院分区：
文献类型：
--
作者：
Fernandes, Michelle Oliveira;Tourtellotte, Warren G.
肌肉拉伸本体感受器（肌纺锤体）是拉伸反射和运动控制所必需的。在许多人类神经病变中都观察到本体感觉异常，但建立和维持肌梭形神经支配和功能的机制仍然知之甚少。在骨骼肌发育过程中，感觉（ia -传入）神经支配诱导接触肌管转化为束内肌纤维，形成拉伸受体核心。转录调节因子Egr3在ia传入接触肌管中通过神经调节蛋白1 (Neuregulin1, Nrg1)/ErbB受体信号传导诱导，在纺锤体形态发生和功能中起重要作用。由于Egr3在发育过程中广泛表达并具有多向性功能，因此Egr3主要在骨骼肌、ia -传入神经元中起作用，还是在髓鞘化ia -传入轴突的雪旺细胞中起作用尚不清楚。在目前的研究中，小鼠细胞特异性消融Egr3表明它在拉伸受体发育中具有骨骼肌自主功能。此外，通过遗传追踪，我们发现ia传入接触性egr3缺陷肌管的诱导数量正常，但它们的发育被阻断以产生一到两条缩短的纤维，这些纤维不能表达一些特有的MyHC蛋白。这些“纺锤体残体”持续到成年，仍然受ia传入神经支配，并表达神经营养蛋白3 (NT3)，这是ia传入神经元存活所必需的。然而，它们不受梭状运动轴突的支配，也不表达对梭状运动神经元存活至关重要的神经胶质源性神经营养因子（GDNF）。这些结果表明，Egr3在调节基因表达，促进正常肌内纤维分化和梭运动神经平衡中具有重要作用。
Muscle stretch proprioceptors (muscle spindles) are required for stretch reflexes and locomotor control. Proprioception abnormalities are observed in many human neuropathies, but the mechanisms involved in establishing and maintaining muscle spindle innervation and function are still poorly understood. During skeletal muscle development, sensory (Ia-afferent) innervation induces contacted myotubes to transform into intrafusal muscle fibers that form the stretch receptor core. The transcriptional regulator Egr3 is induced in Ia-afferent contacted myotubes by Neuregulin1 (Nrg1)/ErbB receptor signaling and it has an essential role in spindle morphogenesis and function. Because Egr3 is widely expressed during development and has a pleiotropic function, whether Egr3 functions primarily in skeletal muscle, Ia-afferent neurons, or in Schwann cells that myelinate Ia-afferent axons remains unresolved. In the present studies, cell-specificablation of Egr3 in mice showed that it has a skeletal muscle autonomous function in stretch receptor development. Moreover, using genetic tracing, we found that Ia-afferent contacted Egr3-deficient myotubes were induced in normal numbers, but their development was blocked to generate one to two shortened fibers that failed to express some characteristic myosin heavy chain (MyHC) proteins. These "spindle remnants" persisted into adulthood, remained innervated by Ia-afferents, and expressed neurotrophin3 (NT3), which is required for Ia-afferent neuron survival. However, they were not innervated by fusimotor axons and they did not express glial derived neurotrophic factor (GDNF), which is essential for fusimotor neuron survival. These results demonstrate that Egr3 has an essential role in regulating gene expression that promotes normal intrafusal muscle fiber differentiation and fusimotor innervation homeostasis.