Spencer Center for Vision Research, Byers Eye Institute, School of Medicine, Stanford University, Palo Alto, CA 94304
Department of Ophthalmology, Louis J. Fox Center for Vision Restoration, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213.
eNeuro. 2021 Feb 11;8(1). doi: 10.1523/ENEURO.0358-20.2020. Print 2021 Jan-Feb.
The failure of adult CNS neurons to survive and regenerate their axons after injury or in neurodegenerative disease remains a major target for basic and clinical neuroscience. Recent data demonstrated in the adult mouse that exogenous expression of Sry-related high-mobility-box 11 (Sox11) promotes optic nerve regeneration after optic nerve injury but exacerbates the death of a subset of retinal ganglion cells (RGCs), α-RGCs. During development, Sox11 is required for RGC differentiation from retinal progenitor cells (RPCs), and we found that mutation of a single residue to prevent SUMOylation at lysine 91 (K91) increased Sox11 nuclear localization and RGC differentiation Here, we explored whether this Sox11 manipulation similarly has stronger effects on RGC survival and optic nerve regeneration. , we found that non-SUMOylatable Sox11 leads to RGC death and suppresses axon outgrowth in primary neurons. We furthermore found that Sox11 more strongly promotes axon regeneration but also increases RGC death after optic nerve injury in the adult mouse. RNA sequence (RNA-seq) data showed that Sox11 and Sox11 increase the expression of key signaling pathway genes associated with axon growth and regeneration but downregulated and expression in RGC cultures, consistent with negatively regulating the survival of α-RGCs and ipRGCs. Thus, Sox11 and its SUMOylation site at K91 regulate gene expression, survival and axon growth in RGCs, and may be explored further as potential regenerative therapies for optic neuropathy.
成年中枢神经系统神经元在受伤或神经退行性疾病后无法存活和再生其轴突，这仍然是基础和临床神经科学的主要目标。最近的数据表明，在成年小鼠中，外源性表达 Sry 相关高迁移率族盒 11（Sox11）可促进视神经损伤后的视神经再生，但会加剧一部分视网膜神经节细胞（RGC），即α-RGC 的死亡。在发育过程中，Sox11 是 RGC 从视网膜祖细胞（RPCs）分化所必需的，我们发现，将一个残基突变为阻止赖氨酸 91（K91）的 SUMO 化可增加 Sox11 的核定位和 RGC 分化。在这里，我们探讨了这种 Sox11 操作是否同样对 RGC 存活和视神经再生有更强的影响。我们发现，非 SUMO 化的 Sox11 导致 RGC 死亡，并抑制原代神经元中的轴突生长。我们还发现，Sox11 更强烈地促进视神经损伤后成年小鼠的轴突再生，但也增加了 RGC 的死亡。RNA 序列（RNA-seq）数据表明，Sox11 和 Sox11 增加了与轴突生长和再生相关的关键信号通路基因的表达，但下调了 RGC 培养物中 和 的表达，这与负调控 α-RGC 和 ipRGC 的存活一致。因此，Sox11 及其 K91 的 SUMO 化位点调节 RGC 中的基因表达、存活和轴突生长，可能进一步作为治疗视神经病变的潜在再生疗法进行探索。
