Ephrin-B Reverse Signaling Is Required for Formation of Strictly Contralateral Auditory Brainstem Pathways
Ephrin-B Reverse Signaling Is Required for Formation of Strictly Contralateral Auditory Brainstem Pathways
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DOI：
10.1523/jneurosci.0386-10.2010
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发表时间：
2010-07-21
影响因子：
5.3
通讯作者：
Cramer, Karina S.
中科院分区：
文献类型：
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作者：
Hsieh, Candace Y.;Nakamura, Paul A.;Cramer, Karina S.
哺乳动物耳蜗腹核(VCN)投射的特异性对声音定位是至关重要的。球状丛状细胞从VCN投射到对侧的斜方体内侧核(MNTB)，但不投射到脑干的同侧，终止于被称为Hold花瓣的大型突触终末。这一途径的精确度对于计算耳间强度差是至关重要的，这是用于声音定位的。这一预测的发展背后的机制还没有完全被理解。在这项研究中，我们测试了Eph受体酪氨酸激酶及其ePhin配体在限制VCN-MNTB投射到对侧的作用。我们发现EphB2和EphB3零突变的小鼠有正常的对侧VCN-MNTB投射，但这些投射在同侧MNTB也有显著数量的异常侧支。这些异常分支终止于MNTB内的肾盏终末。类似的同侧投射也出现在ePhrin-B2突变的小鼠身上。在这两个小鼠品系中，同侧投射与正常对侧投射同时形成，并未在发育后期消除。然而，突变只影响EphB2细胞内结构域的小鼠有正常的、严格对侧的VCN-MNTB投射。表达研究表明，EphB2在VCN轴突中表达，ePhin-B2在MNTB中表达。综上所述，这些数据表明，EphB2-ePhin-B2反向信号是防止同侧VCN-MNTB投射形成所必需的，并且这种信号是非细胞自主运行的。
Specificity in the projections from the mammalian ventral cochlear nucleus (VCN) is essential for sound localization. Globular bushy cells project from the VCN to the medial nucleus of the trapezoid body (MNTB) on the contralateral, but not the ipsilateral, side of the brainstem, terminating in large synaptic endings known as calyces of Held. The precision in this pathway is critical for the computation of interaural intensity differences, which are used in sound localization. The mechanisms underlying the development of this projection are not completely understood. In this study, we tested the role of Eph receptor tyrosine kinases and their ephrin ligands in limiting the VCN-MNTB projection to the contralateral side. We found that mice with null mutations in EphB2 and EphB3 had normal contralateral VCN-MNTB projections, yet these projections also had significant numbers of aberrant collateral branches in the ipsilateral MNTB. These aberrant branches ended in calyceal terminations in MNTB. Similar ipsilateral projections were seen in mice with mutations in ephrin-B2. In both of these mouse lines, ipsilateral projections formed concurrently with normal contralateral projections and were not eliminated later in development. However, mice with mutations that affected only the intracellular domain of EphB2 had normal, strictly contralateral VCN-MNTB projections. Expression studies showed that EphB2 is expressed in VCN axons and ephrin-B2 is expressed in MNTB. Together, these data suggest that EphB2-ephrin-B2 reverse signaling is required to prevent the formation of ipsilateral VCN-MNTB projections and that this signaling operates non-cell autonomously.