Hsieh Candace Y, Hong Cindy T, Cramer Karina S
Department of Neurobiology and Behavior, University of California Irvine, Irvine, California 92697-4550, USA.
J Comp Neurol. 2007 Oct 10;504(5):508-18. doi: 10.1002/cne.21465.
Axonal selection of ipsilateral and/or contralateral targets is essential for integrating bilateral sensory information and for coordinated movement. The molecular processes that determine ipsilateral and contralateral target choice are not fully understood. We examined this target selection in the developing auditory brainstem. Ventral cochlear nucleus (VCN) axons normally project to the medial nucleus of the trapezoid body (MNTB) only on the contralateral side. However, after unilateral removal of cochlear input in neonates, we found that axons from the unoperated VCN sprout and project to MNTB bilaterally. We found that EphA4 is expressed in the mouse auditory brainstem during development and during a sensitive period for ipsilateral sprouting, so we hypothesized that deletion of the Eph receptor EphA4 would impair target selection in these auditory pathways. Lipophilic dyes were used to evaluate quantitatively the brainstem projections in wild-type and EphA4-null mice. VCN-MNTB projections in EphA4-null mice were strictly contralateral, as in wild-type mice. However, after deafferentation, EphA4-null mice had a significant, threefold increase in the proportion of axons from the intact VCN that sprouted into ipsilateral MNTB compared with wild-type mice. Heterozygous mice had a twofold increase in these projections. These results demonstrate that EphA4 influences auditory brainstem circuitry selectively in response to deafferentation. Although this axon guidance molecule is not by itself necessary for appropriate target choice during normal development, it is a strong determinant of ipsilateral vs. contralateral target choice during deafferentation-induced plasticity.
轴突对同侧和/或对侧靶标的选择对于整合双侧感觉信息和协调运动至关重要。决定同侧和对侧靶标选择的分子过程尚未完全了解。我们在发育中的听觉脑干中研究了这种靶标选择。腹侧耳蜗核（VCN）轴突通常仅向对侧的斜方体内侧核（MNTB）投射。然而，在新生小鼠单侧去除耳蜗输入后，我们发现未手术侧VCN的轴突发芽并双侧投射到MNTB。我们发现EphA4在小鼠听觉脑干发育期间以及同侧发芽的敏感期表达，因此我们假设Eph受体EphA4的缺失会损害这些听觉通路中的靶标选择。使用亲脂性染料定量评估野生型和EphA4基因敲除小鼠的脑干投射。与野生型小鼠一样，EphA4基因敲除小鼠中的VCN-MNTB投射严格为对侧。然而，去传入神经后，与野生型小鼠相比，EphA4基因敲除小鼠中来自完整VCN的轴突发芽进入同侧MNTB的比例显著增加了三倍。杂合子小鼠的这些投射增加了两倍。这些结果表明，EphA4在去传入神经反应中选择性地影响听觉脑干回路。虽然这种轴突导向分子本身在正常发育过程中对于适当的靶标选择不是必需的，但它是去传入神经诱导的可塑性过程中同侧与对侧靶标选择的一个重要决定因素。
