Oster Stephen F, Bodeker MacDara O, He Fengling, Sretavan David W
Department of Ophthalmology, Medical Scientist Training Program, University of California San Francisco, CA 94143, USA.
Development. 2003 Feb;130(4):775-84. doi: 10.1242/dev.00299.
Retinal axon pathfinding from the retina into the optic nerve involves the growth promoting axon guidance molecules L1, laminin and netrin 1, each of which governs axon behavior at specific regions along the retinal pathway. In identifying additional molecules regulating this process during embryonic mouse development, we found that transmembrane Semaphorin5A mRNA and protein was specifically expressed in neuroepithelial cells surrounding retinal axons at the optic disc and along the optic nerve. Given that growth cone responses to a specific guidance molecule can be altered by co-exposure to a second guidance cue, we examined whether retinal axon responses to Sema5A were modulated by other guidance signals axons encountered along the retinal pathway. In growth cone collapse, substratum choice and neurite outgrowth assays, Sema5A triggered an invariant inhibitory response in the context of L1, laminin, or netrin 1 signaling, suggesting that Sema5A inhibited retinal axons throughout their course at the optic disc and nerve. Antibody-perturbation studies in living embryo preparations showed that blocking of Sema5A function led to retinal axons straying out of the optic nerve bundle, indicating that Sema5A normally helped ensheath the retinal pathway. Thus, development of some CNS nerves requires inhibitory sheaths to maintain integrity. Furthermore, this function is accomplished using molecules such as Sema5A that exhibit conserved inhibitory responses in the presence of co-impinging signals from multiple families of guidance molecules.
视网膜轴突从视网膜向视神经的路径寻找涉及促进生长的轴突导向分子L1、层粘连蛋白和netrin 1，每一种分子都在视网膜路径的特定区域控制轴突行为。在确定胚胎小鼠发育过程中调节这一过程的其他分子时，我们发现跨膜信号素5A（Semaphorin5A）的mRNA和蛋白在视盘和视神经处围绕视网膜轴突的神经上皮细胞中特异性表达。鉴于生长锥对特定导向分子的反应可因同时暴露于第二种导向信号而改变，我们研究了视网膜轴突对信号素5A的反应是否受到沿视网膜路径遇到的其他导向信号的调节。在生长锥塌陷、底物选择和神经突生长试验中，信号素5A在L1、层粘连蛋白或netrin 1信号传导的背景下引发了不变的抑制反应，这表明信号素5A在视盘和神经的整个行程中抑制视网膜轴突。对活胚胎制剂进行的抗体干扰研究表明，阻断信号素5A的功能会导致视网膜轴突偏离视神经束，这表明信号素5A通常有助于包裹视网膜路径。因此，一些中枢神经系统神经的发育需要抑制性鞘来维持完整性。此外，这种功能是通过使用信号素5A等分子来实现的，这些分子在存在来自多个导向分子家族的共同作用信号时表现出保守的抑制反应。
