Chen Yuanyuan Y, Hehr Carrie L, Atkinson-Leadbeater Karen, Hocking Jennifer C, McFarlane Sarah
Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada T2N 4N1.
J Neurosci. 2007 Aug 1;27(31):8448-56. doi: 10.1523/JNEUROSCI.1841-07.2007.
The role of extrinsic cues in guiding developing axons is well established; however, the means by which the activity of these extrinsic cues is regulated is poorly understood. A disintegrin and metalloproteinase (ADAM) enzymes are Zn-dependent proteinases that can cleave guidance cues or their receptors in vitro. Here, we identify the first example of a metalloproteinase that functions in vertebrate axon guidance in vivo. Specifically, ADAM10 is required for formation of the optic projection by Xenopus retinal ganglion cell (RGC) axons. Xadam10 mRNA is expressed in the dorsal neuroepithelium through which RGC axons extend. Pharmacological or molecular inhibition of ADAM10 within the brain each resulted in a failure of RGC axons to recognize their target. In contrast, molecular inhibition of ADAM10 within the RGC axons themselves had no effect. These data argue strongly that in the dorsal brain ADAM10 acts cell non-autonomously to regulate the guidance of RGC axons.
外在信号在引导轴突发育过程中的作用已得到充分证实；然而，这些外在信号的活性是如何被调控的，目前还知之甚少。解整合素和金属蛋白酶（ADAM）是一类依赖锌的蛋白酶，它们在体外能够切割引导信号或其受体。在此，我们鉴定出了首个在脊椎动物体内轴突导向中发挥作用的金属蛋白酶实例。具体而言，非洲爪蟾视网膜神经节细胞（RGC）轴突形成视投射需要ADAM10。Xadam10 mRNA在RGC轴突延伸穿过的背侧神经上皮中表达。对脑内ADAM10进行药理学或分子抑制均导致RGC轴突无法识别其靶标。相比之下，对RGC轴突自身进行ADAM10分子抑制则没有影响。这些数据有力地表明，在背侧脑区，ADAM10以非细胞自主方式发挥作用来调控RGC轴突的导向。
