Center for Brain Science and Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA.
Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
Neuron. 2019 Dec 18;104(6):1039-1055.e12. doi: 10.1016/j.neuron.2019.11.006. Epub 2019 Nov 26.
Neuronal types in the central nervous system differ dramatically in their resilience to injury or other insults. Here we studied the selective resilience of mouse retinal ganglion cells (RGCs) following optic nerve crush (ONC), which severs their axons and leads to death of ∼80% of RGCs within 2 weeks. To identify expression programs associated with differential resilience, we first used single-cell RNA-seq (scRNA-seq) to generate a comprehensive molecular atlas of 46 RGC types in adult retina. We then tracked their survival after ONC; characterized transcriptomic, physiological, and morphological changes that preceded degeneration; and identified genes selectively expressed by each type. Finally, using loss- and gain-of-function assays in vivo, we showed that manipulating some of these genes improved neuronal survival and axon regeneration following ONC. This study provides a systematic framework for parsing type-specific responses to injury and demonstrates that differential gene expression can be used to reveal molecular targets for intervention.
中枢神经系统中的神经元类型在对损伤或其他损伤的抵抗力方面有很大差异。在这里，我们研究了视神经挤压（ONC）后小鼠视网膜神经节细胞（RGC）的选择性恢复能力，ONC 会切断它们的轴突，并导致大约 80%的 RGC 在 2 周内死亡。为了确定与差异恢复能力相关的表达程序，我们首先使用单细胞 RNA-seq（scRNA-seq）生成成年视网膜中 46 种 RGC 类型的综合分子图谱。然后，我们在 ONC 后追踪它们的存活情况；描述了退化前转录组学、生理学和形态学的变化；并确定了每种类型选择性表达的基因。最后，通过体内的失活和功能获得实验，我们表明操纵其中一些基因可以改善 ONC 后神经元的存活和轴突再生。这项研究为解析特定类型对损伤的反应提供了一个系统的框架，并表明差异表达的基因可用于揭示干预的分子靶点。
