PDF(Pubmed)
Abstract：
Semaphorins and Plexins form ligand/receptor pairs that are crucial for a wide range of developmental processes from cell proliferation to axon guidance. The ability of semaphorins to act both as signaling receptors and ligands yields a multitude of responses. Here, we describe a novel role for Semaphorin-6D (Sema6D) and Plexin-A1 in the positioning and targeting of retinogeniculate axons. In Plexin-A1 or Sema6D mutant mice of either sex, the optic tract courses through, rather than along, the border of the dorsal lateral geniculate nucleus (dLGN), and some retinal axons ectopically arborize adjacent and lateral to the optic tract rather than defasciculating and entering the target region. We find that Sema6D and Plexin-A1 act together in a dose-dependent manner, as the number of the ectopic retinal projections is altered in proportion to the level of Sema6D or Plexin-A1 expression. Moreover, using retinal in utero electroporation of Sema6D or Plexin-A1 shRNA, we show that Sema6D and Plexin-A1 are both required in retinal ganglion cells for axon positioning and targeting. Strikingly, nonelectroporated retinal ganglion cell axons also mistarget in the tract region, indicating that Sema6D and Plexin-A1 can act non-cell-autonomously, potentially through axon-axon interactions. These data provide novel evidence for a dose-dependent and non-cell-autonomous role for Sema6D and Plexin-A1 in retinal axon organization in the optic tract and dLGN.SIGNIFICANCE STATEMENT Before innervating their central brain targets, retinal ganglion cell axons fasciculate in the optic tract and then branch and arborize in their target areas. Upon deletion of the guidance molecules Plexin-A1 or Semaphorin-6D, the optic tract becomes disorganized near and extends within the dorsal lateral geniculate nucleus. In addition, some retinal axons form ectopic aggregates within the defasciculated tract. Sema6D and Plexin-A1 act together as a receptor-ligand pair in a dose-dependent manner, and non-cell-autonomously, to produce this developmental aberration. Such a phenotype highlights an underappreciated role for axon guidance molecules in tract cohesion and appropriate defasciculation near, and arborization within, targets.
摘要：
信号素和神经丛蛋白形成配体/受体对,其对于从细胞增殖到轴突导向的宽范围的发育过程至关重要。信号素作为信号传导受体和配体的能力产生多种反应。这里,我们描述了Semaphorin-6D(Sema6D)和Plexin-A1在视网膜生成轴突的定位和靶向中的新作用。在Plexin-A1或Sema6D突变小鼠中，视神经束穿过而不是位于背外侧膝状核（dLGN）的边界；一些视网膜轴突在视神经束附近和外侧外翻，而不是蠕动并进入目标区域。我们发现Sema6D和Plexin-A1一起作用，并以剂量依赖的方式，因为异位视网膜投影的数量与Sema6D或Plexin-A1表达水平成比例地改变。此外，使用Sema6D或Plexin-A1shRNA的子宫内视网膜电穿孔，我们发现Sema6D和Plexin-A1都是视网膜神经节细胞(RGCs)轴突定位和靶向所必需的.引人注目的是，非电穿孔的RGC轴突也在束区不一致，表明Sema6D和Plexin-A1可以非细胞自主作用，可能通过轴突-轴突相互作用。这些数据为Sema6D和Plexin-A1在视神经束和dLGN的视网膜轴突组织中的剂量依赖性和非细胞自主作用提供了新的证据。重要声明：在支配他们的中枢神经目标之前，视网膜神经节细胞（RGC）轴突在视神经束中成束，然后在目标区域分支和树干。在缺失引导分子Plexin-A1或Semaphorin-6D时，视神经束在背侧外侧膝状核附近变得杂乱无章，并在其中延伸。此外,一些视网膜轴突在血管内形成异位聚集体。Sema6D和Plexin-A1以剂量依赖性方式一起作为受体-配体对，非细胞自主，产生这种发育异常。这种表型突出了轴突导向分子在束线内聚和目标附近的适当疏解以及目标内的乔伯化中的作用。
