Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, OH, 44106, USA.
Department of Hand and Foot Surgery, China-Japan Union Hospital of Jilin University, Changchun, China.
Nat Commun. 2023 Feb 10;14(1):744. doi: 10.1038/s41467-023-36454-8.
Proprioception is sensed by muscle spindles for precise locomotion and body posture. Unlike the neuromuscular junction (NMJ) for muscle contraction which has been well studied, mechanisms of spindle formation are not well understood. Here we show that sensory nerve terminals are disrupted by the mutation of Lrp4, a gene required for NMJ formation; inducible knockout of Lrp4 in adult mice impairs sensory synapses and movement coordination, suggesting that LRP4 is required for spindle formation and maintenance. LRP4 is critical to the expression of Egr3 during development; in adult mice, it interacts in trans with APP and APLP2 on sensory terminals. Finally, spindle sensory endings and function are impaired in aged mice, deficits that could be diminished by LRP4 expression. These observations uncovered LRP4 as an unexpected regulator of muscle spindle formation and maintenance in adult and aged animals and shed light on potential pathological mechanisms of abnormal muscle proprioception.
本体感觉由肌梭感知，以实现精确的运动和身体姿势。与肌肉收缩的神经肌肉接头（NMJ）不同，肌梭的形成机制尚不清楚。在这里，我们发现感觉神经末梢被 Lrp4 突变破坏，Lrp4 是 NMJ 形成所必需的基因；成年小鼠中 Lrp4 的诱导性敲除会损害感觉突触和运动协调，表明 LRP4 是形成和维持肌梭所必需的。LRP4 对 Egr3 在发育过程中的表达至关重要；在成年小鼠中，它在感觉末梢上与 APP 和 APLP2 反式相互作用。最后，老年小鼠的肌梭感觉末梢和功能受损，LRP4 的表达可减轻这些缺陷。这些观察结果揭示了 LRP4 是成年和老年动物肌梭形成和维持的意外调节剂，并为异常肌肉本体感觉的潜在病理机制提供了线索。
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