Höpker V H, Shewan D, Tessier-Lavigne M, Poo M, Holt C
Department of Biology, University of California at San Diego, La Jolla 92093-0357, USA.
Nature. 1999 Sep 2;401(6748):69-73. doi: 10.1038/43441.
Growing axons are guided by both diffusible and substrate-bound factors. Growth cones of retinal neurons exhibit chemoattractive turning towards the diffusible factor netrin-1 in vitro and are guided into the optic nerve head (ONH) by localized netrin-1. Here we report that, in Xenopus, laminin-1 from the extracellular matrix (ECM), converts netrin-mediated attraction into repulsion. A soluble peptide fragment of laminin-1 (YIGSR) mimics this laminin-induced conversion. Low levels of cyclic AMP in growth cones also lead to the conversion of netrin-induced attraction into repulsion, and we show that the amount of cAMP decreases in the presence of laminin-1 or YIGSR, suggesting a possible mechanism for laminin's effect. At the netrin-1-rich ONH, where axons turn sharply to leave the eye, laminin-1 is confined to the retinal surface. Repulsion from the region in which laminin and netrin are coexpressed may help to drive axons into the region where only netrin is present, providing a mechanism for their escape from the retinal surface. Consistent with this idea, YIGSR peptides applied to the developing retina cause axons to be misdirected at the ONH. These findings indicate that ECM molecules not only promote axon outgrowth, but also modify the behaviour of growth cones in response to diffusible guidance cues.
正在生长的轴突由可扩散因子和与底物结合的因子引导。视网膜神经元的生长锥在体外对可扩散因子netrin-1表现出化学吸引性转向，并被局部的netrin-1引导进入视神经乳头（ONH）。在此我们报告，在非洲爪蟾中，细胞外基质（ECM）中的层粘连蛋白-1将netrin介导的吸引转化为排斥。层粘连蛋白-1的一个可溶性肽片段（YIGSR）模拟了这种层粘连蛋白诱导的转化。生长锥中低水平的环磷酸腺苷（cAMP）也会导致netrin诱导的吸引转化为排斥，并且我们发现，在存在层粘连蛋白-1或YIGSR的情况下，cAMP的量会减少，这提示了层粘连蛋白作用的一种可能机制。在富含netrin-1的视神经乳头处，轴突在此急剧转向以离开眼睛，层粘连蛋白-1局限于视网膜表面。来自层粘连蛋白和netrin共表达区域的排斥可能有助于驱使轴突进入仅存在netrin的区域，为它们从视网膜表面逃逸提供一种机制。与此观点一致，将YIGSR肽应用于发育中的视网膜会导致轴突在视神经乳头处被错误引导。这些发现表明，ECM分子不仅促进轴突生长，还会根据可扩散的引导信号改变生长锥的行为。
