Immature astrocytes and blood vessels enter the developing mammalian retina at the optic nerve head and migrate peripherally to colonize the entire retinal nerve fiber layer (RNFL). Retinal vascularization is arrested in retinopathy of prematurity (ROP), a major cause of bilateral blindness in children. Despite their importance in normal development and ROP, the factors that control vascularization of the retina remain poorly understood. Because astrocytes form a reticular network that appears to provide a substrate for migrating endothelial cells, they have long been proposed to guide angiogenesis. However, whether astrocytes do in fact impose a spatial pattern on developing vessels remains unclear, and how astrocytes themselves are guided is unknown. Here we explore the cellular mechanisms that ensure complete retinal coverage by astrocytes and blood vessels in mouse. We find that migrating astrocytes associate closely with the axons of retinal ganglion cells (RGCs), their neighbors in the RNFL. Analysis of Robo1; Robo2 mutants, in which RGC axon guidance is disrupted, and Math5 (Atoh7) mutants, which lack RGCs, reveals that RGCs provide directional information to migrating astrocytes that sets them on a centrifugal trajectory. Without this guidance, astrocytes exhibit polarization defects, fail to colonize the peripheral retina, and display abnormal fine-scale spatial patterning. Furthermore, using cell type-specific chemical-genetic tools to selectively ablate astrocytes, we show that the astrocyte template is required for angiogenesis and vessel patterning. Our results are consistent with a model whereby RGC axons guide formation of an astrocytic network that subsequently directs vessel development.

中文翻译：

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星形胶质细胞跟随神经节细胞轴突在视网膜发育过程中建立血管生成模板。

未成熟的星形胶质细胞和血管在视神经乳头进入正在发育的哺乳动物视网膜，并向周边迁移以定殖整个视网膜神经纤维层（RNFL）。早产儿视网膜病变 (ROP) 导致视网膜血管形成停滞，这是儿童双侧失明的主要原因。尽管控制视网膜血管形成的因素对于正常发育和 ROP 很重要，但人们对它们仍知之甚少。由于星形胶质细胞形成网状网络，似乎为迁移内皮细胞提供基质，因此长期以来一直有人提出它们可以引导血管生成。然而，星形胶质细胞实际上是否确实对发育中的血管施加了空间模式仍不清楚，星形胶质细胞本身如何被引导尚不清楚。在这里，我们探讨了确保小鼠星形胶质细胞和血管完全覆盖视网膜的细胞机制。我们发现迁移的星形胶质细胞与视网膜神经节细胞（RGC）的轴突密切相关，RGC 是它们在 RNFL 中的邻居。Robo1分析；Robo2 突变体（其中 RGC 轴突引导被破坏）和 Math5 (Atoh7) 突变体（缺乏 RGC）表明，RGC 为迁移星形胶质细胞提供方向信息，使它们处于离心轨迹上。如果没有这种指导，星形胶质细胞就会表现出偏振缺陷，无法在视网膜周边定植，并表现出异常的精细空间图案。此外，使用细胞类型特异性化学遗传工具选择性消融星形胶质细胞，我们表明星形胶质细胞模板是血管生成和血管图案化所必需的。我们的结果与 RGC 轴突引导星形胶质细胞网络形成的模型一致，该网络随后指导血管发育。