Oliveira Fernandes Michelle, Tourtellotte Warren G
Department of Pathology (Division of Neuropathology), Northwestern University Driskill Graduate Program, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611.
Department of Pathology (Division of Neuropathology), Department of Neurology, and Northwestern University Driskill Graduate Program, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611
J Neurosci. 2015 Apr 8;35(14):5566-78. doi: 10.1523/JNEUROSCI.0241-15.2015.
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-specific ablation 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.
肌肉伸展本体感受器（肌梭）对于伸展反射和运动控制至关重要。在许多人类神经病变中都观察到了本体感觉异常，但建立和维持肌梭神经支配及功能的机制仍知之甚少。在骨骼肌发育过程中，感觉（Ia传入）神经支配诱导与之接触的肌管转化为形成伸展感受器核心的梭内肌纤维。转录调节因子Egr3在Ia传入接触的肌管中由神经调节蛋白1（Nrg1）/ErbB受体信号诱导产生，并且在纺锤体形态发生和功能中起关键作用。由于Egr3在发育过程中广泛表达且具有多效性功能，Egr3主要在骨骼肌、Ia传入神经元或使Ia传入轴突髓鞘化的施万细胞中发挥作用仍未明确。在本研究中，小鼠中Egr3的细胞特异性缺失表明其在伸展感受器发育中具有骨骼肌自主功能。此外，通过基因追踪，我们发现Ia传入接触的Egr3缺陷型肌管数量正常诱导产生，但它们的发育受阻，只能生成一到两根缩短的纤维，这些纤维无法表达某些特征性的肌球蛋白重链（MyHC）蛋白。这些“纺锤体残余物”持续到成年期，仍由Ia传入神经支配，并表达Ia传入神经元存活所需的神经营养因子3（NT3）。然而，它们未被梭外运动轴突支配，也不表达对梭外运动神经元存活至关重要的胶质细胞源性神经营养因子（GDNF）。这些结果表明，Egr3在调节促进正常梭内肌纤维分化和梭外运动神经支配稳态的基因表达中起关键作用。
