Matrix metalloproteinases are required for retinal ganglion cell axon guidance at select decision points
Matrix metalloproteinases are required for retinal ganglion cell axon guidance at select decision points
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DOI：
10.1242/dev.01908
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发表时间：
2005-08-01
期刊：
影响因子：
4.6
通讯作者：
McFarlane, S
中科院分区：
文献类型：
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作者：
Hehr, CL;Hocking, JC;McFarlane, S
轴突从环境中的外在线索接收指导信息，以达到目标。在非洲爪蟾中，视网膜神经节细胞 (RGC) 轴突在穿过大脑的过程中做出三个关键的指导决策。首先，它们在视交叉处穿过大脑的对侧。其次，它们在中脑中向尾部转动。最后，他们必须认识到视顶盖是他们的目标。基质金属蛋白酶 (MMP) 以及解整合素和金属蛋白酶 (ADAM) 家族是锌 (Zn) 依赖性蛋白水解酶。后者在轴突引导中发挥作用，但尚未确定 MMP 家族具有类似的作用。我们之前的工作表明金属蛋白酶参与了非洲爪蟾 RGC 轴突的指导决策。为了具体测试 MMP 的重要性，我们使用了两种不同的体内暴露脑制剂，其中 RGC 轴突在到达视交叉或穿过间脑延伸至视顶盖时暴露于 MMP 特异性药理学抑制剂 (SB-3CT)。有趣的是，SB-3CT 仅影响了两个引导决策，在视交叉和顶盖处存在错误路由缺陷。只有在较高浓度下，RGC 轴突延伸才会受损。这些数据表明 MMP 在脊椎动物轴突的引导中发挥作用，并表明不同的金属蛋白酶在不同的选择点发挥调节轴突行为的作用：MMP 在视交叉和目标的引导中很重要，而轴突需要不同的 MMP 或 ADAM 才能在中脑中转动。
Axons receive guidance information from extrinsic cues in their environment in order to reach their targets. In the frog Xenopus laevis, retinal ganglion cell (RGC) axons make three key guidance decisions en route through the brain. First, they cross to the contralateral side of the brain at the optic chiasm. Second, they turn caudally in the middiencephalon. Finally, they must recognize the optic tectum as their target. The matrix metalloproteinase (MMP) and a disintegrin and metalloproteinase (ADAM) families are zinc (Zn)-dependent proteolytic enzymes. The latter functions in axon guidance, but a similar role has not yet been identified for the MMP family. Our previous work implicated metalloproteinases in the guidance decisions made by Xenopus RGC axons. To test specifically the importance of MMPs, we used two different in vivo exposed brain preparations in which RGC axons were exposed to an MMP-specific pharmacological inhibitor (SB-3CT), either as they reached the optic chiasm or as they extended through the diencephalon en route to the optic tectum. Interestingly, SB-3CT affected only two of the guidance decisions, with misrouting defects at the optic chiasm and tectum. Only at higher concentrations was RGC axon extension also impaired. These data implicate MMPs in the guidance of vertebrate axons, and suggest that different metalloproteinases function to regulate axon behaviour at distinct choice points: an MMP is important in guidance at the optic chiasm and the target, while either a different MMP or an ADAM is required for axons to make the turn in the mid-diencephalon.