Frisén J, Yates P A, McLaughlin T, Friedman G C, O'Leary D D, Barbacid M
Department of Molecular Oncology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543, USA.
Neuron. 1998 Feb;20(2):235-43. doi: 10.1016/s0896-6273(00)80452-3.
Ephrin-A5 (AL-1/RAGS), a ligand for Eph receptor tyrosine kinases, repels retinal axons in vitro and has a graded expression in the superior colliculus (SC), the major midbrain target of retinal ganglion cells. These properties implicate ephrin-A5 in the formation of topographic maps, a fundamental organizational feature of the nervous system. To test this hypothesis, we generated mice lacking ephrin-A5. The majority of ephrin-A5-/- mice develop to adulthood, are morphologically intact, and have normal anterior-posterior patterning of the midbrain. However, within the SC, retinal axons establish and maintain dense arborizations at topographically incorrect sites that correlate with locations of low expression of the related ligand ephrin-A2. In addition, retinal axons transiently overshoot the SC and extend aberrantly into the inferior colliculus (IC). This defect is consistent with the high level of ephrin-A5 expression in the IC and the finding that retinal axon growth on membranes from wild-type IC is inhibited relative to that on membranes from ephrin-A5-/- IC. These findings show that ephrin-A5 is required for the proper guidance and mapping of retinal axons in the mammalian midbrain.
Ephrin-A5（AL-1/RAGS）是Eph受体酪氨酸激酶的一种配体，在体外可排斥视网膜轴突，并且在上丘（SC）中呈梯度表达，上丘是视网膜神经节细胞的主要中脑靶区。这些特性表明ephrin-A5参与了拓扑图谱的形成，拓扑图谱是神经系统的一个基本组织特征。为了验证这一假设，我们培育出了缺乏ephrin-A5的小鼠。大多数ephrin-A5基因敲除小鼠发育至成年，形态完整，中脑的前后模式正常。然而，在SC内，视网膜轴突在拓扑位置不正确的部位建立并维持密集的分支，这些部位与相关配体ephrin-A2低表达的位置相关。此外，视网膜轴突会短暂地越过SC并异常延伸至下丘（IC）。这一缺陷与IC中ephrin-A5的高表达水平以及相对于来自ephrin-A5基因敲除IC的膜，野生型IC膜上视网膜轴突生长受到抑制的发现一致。这些发现表明，ephrin-A5是哺乳动物中脑视网膜轴突正确导向和图谱形成所必需的。
