Differential regulation of AChR clustering in the polar and equatorial region of murine muscle spindles
Differential regulation of AChR clustering in the polar and equatorial region of murine muscle spindles
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DOI：
10.1111/ejn.12768
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发表时间：
2015-01-01
影响因子：
3.4
通讯作者：
Kroeger, Stephan
中科院分区：
文献类型：
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作者：
Zhang, Yina;Lin, Shuo;Kroeger, Stephan
肌梭内纤维在中央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。我们以前证明，这两个神经元肌肉接触网站含有胆碱能突触样专业化，包括聚集的烟碱乙酰胆碱受体（AChR）。在这项研究中，我们测试的假设，聚集蛋白及其受体复合物（LRP 4和酪氨酸激酶MuSK组成）参与AChR在肌梭中的聚集，类似于它们在神经肌肉接头中的作用。我们发现，聚集蛋白，MuSK和LRP 4集中在梭内纤维和感觉和运动神经元之间的接触部位，分别，它们在背根神经节的本体感受神经元的细胞体中表达。此外，聚集蛋白和LRP 4，但不是MuSK，在运动神经元细胞体中的脊髓腹角的表达。在聚集蛋白和MuSK缺陷小鼠中，AChR聚集体不存在于极区。相反，在感觉神经元与梭内肌纤维接触的中央区域的AChRs的亚细胞浓度显然不受影响。聚集蛋白（-/-）小鼠体内骨骼肌特异性表达的迷你聚集蛋白足以恢复运动神经元终板的形成。这些结果表明，聚集蛋白和MuSK的运动神经元终板的形成过程中的主要决定因素，但出现AChRs的聚集在中央区域的争议。因此，我们的研究结果表明不同的分子机制AChR集群内两个域的梭内纤维。
Intrafusal fibers of muscle spindles are innervated in the central region by afferent sensory axons and at both polar regions by efferent -motoneurons. We previously demonstrated that both neuron-muscle contact sites contain cholinergic synapse-like specialisation, including aggregates of the nicotinic acetylcholine receptor (AChR). In this study we tested the hypothesis that agrin and its receptor complex (consisting of LRP4 and the tyrosine kinase MuSK) are involved in the aggregation of AChRs in muscle spindles, similar to their role at the neuromuscular junction. We show that agrin, MuSK and LRP4 are concentrated at the contact site between the intrafusal fibers and the sensory- and -motoneuron, respectively, and that they are expressed in the cell bodies of proprioceptive neurons in dorsal root ganglia. Moreover, agrin and LRP4, but not MuSK, are expressed in -motoneuron cell bodies in the ventral horn of the spinal cord. In agrin- and in MuSK-deficient mice, AChR aggregates are absent from the polar regions. In contrast, the subcellular concentration of AChRs in the central region where the sensory neuron contacts the intrafusal muscle fiber is apparently unaffected. Skeletal muscle-specific expression of miniagrin in agrin(-/-) mice in vivo is sufficient to restore the formation of -motoneuron endplates. These results show that agrin and MuSK are major determinants during the formation of -motoneuron endplates but appear dispensable for the aggregation of AChRs at the central region. Our results therefore suggest different molecular mechanisms for AChR clustering within two domains of intrafusal fibers.