A critical and previously unsuspected role for doublecortin at the neuromuscular junction in mouse and human
A critical and previously unsuspected role for doublecortin at the neuromuscular junction in mouse and human
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DOI：
10.1016/j.nmd.2015.01.012
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发表时间：
2015-06-01
影响因子：
2.8
通讯作者：
Legay, C.
中科院分区：
文献类型：
--
作者：
Bourgeois, F.;Messeant, J.;Legay, C.
微管相关蛋白doublecortin（DCX）的突变导致半合子男性的I型（X连锁或XLIS）无脑畸形和女性的皮质下带状异位（SBH），发育过程中神经元迁移缺陷影响皮质分层。我们发现，除了其在大脑的迁移神经元中的良好表达外，doublecortin（小鼠中的Dcx）还在胚胎神经肌肉接头（NMJ）的运动神经元和骨骼肌中表达，从而提高了在突触发生中发挥作用的可能性。胚胎小鼠膈肌的整装制剂的研究表明，Dcx的损失导致异常的突触前分支和神经支配的乙酰胆碱受体（AChR）集群以外的短轴突延伸的发生率显着增加在发展中的NMI。这种表型虽然相对温和，但表明Dcx有助于在突触处的停止/稳定信号，这通常限制了在与突触后元件建立突触接触后的进一步轴突生长。重要的是，我们还确定了一个16岁的女性SBH患者的肌肉活检异常和失神经支配的NMJ，表现出深刻的突触前和突触后形态缺陷。总的来说，这些综合结果指出了双皮质素在NMJ形成中的关键作用。(C)2015 Elsevier B. V.版权所有。
Mutations in the microtubule-associated protein doublecortin (DCX) cause type I (X-linked or XLIS) lissencephaly in hemizygous males and subcortical band heterotopia (SBH) in females, with defects in neuron migration during development affecting cortical lamination. We found that besides its well-established expression in migrating neurons of the brain, doublecortin (Dcx in mice) is also expressed in motor neurons and skeletal muscle in embryonic neuromuscular junctions (NMJs), raising the possibility of a role in synaptogenesis. Studies with whole-mount preparations of embryonic mouse diaphragm revealed that loss of Dcx leads to abnormal presynaptic arborization and a significantly increased incidence of short axonal extensions beyond innervated acetylcholine receptor (AChR) clusters in the developing NMI. This phenotype, albeit relatively mild, suggests that Dcx contributes to a stop/stabilizing signal at the synapse, which normally limits further axonal growth following establishment of synaptic contact with the postsynaptic element. Importantly, we also identified abnormal and denervated NMJs in a muscle biopsy from a 16-year-old female patient with SBH, showing both profound presynaptic and postsynaptic morphological defects. Overall, these combined results point to a critical role of doublecortin in the formation of the NMJ. (C) 2015 Elsevier B.V. All rights reserved.