Department of Anaesthesiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
Proc Natl Acad Sci U S A. 2020 Feb 25;117(8):4199-4210. doi: 10.1073/pnas.1916164117. Epub 2020 Feb 6.
The transcription factor Sox10 is a key regulator in the fate determination of a subpopulation of multipotent trunk neural crest (NC) progenitors toward glial cells instead of sensory neurons in the dorsal root ganglia (DRG). However, the mechanism by which Sox10 regulates glial cell fate commitment during lineage segregation remains poorly understood. In our study, we showed that the neurogenic determinant Neurogenin 2 (Neurog2) exhibited transient overlapping expression with Sox10 in avian trunk NC progenitors, which progressively underwent lineage segregation during migration toward the forming DRG. Gain- and loss-of-function studies revealed that the temporary expression of Neurog2 was due to Sox10 regulation of its protein stability. Transcriptional profiling identified Sox10-regulated F-box only protein (Fbxo9), which is an SCF (Skp1-Cul-F-box)-type ubiquitin ligase for Neurog2. Consistently, overexpression of Fbxo9 in NC progenitors down-regulated Neurog2 protein expression through ubiquitination and promoted the glial lineage at the expense of neuronal differentiation, whereas Fbxo9 knockdown resulted in the opposite phenomenon. Mechanistically, we found that Fbxo9 interacted with Neurog2 to promote its destabilization through the F-box motif. Finally, epistasis analysis further demonstrated that Fbxo9 and probably other F-box members mediated the role of Sox10 in destabilizing Neurog2 protein and directing the lineage of NC progenitors toward glial cells rather than sensory neurons. Altogether, these findings unravel a Sox10-Fbxo9 regulatory axis in promoting the glial fate of NC progenitors through Neurog2 destabilization.
转录因子 Sox10 是一群多能性主干神经嵴 (NC) 祖细胞向背根神经节 (DRG) 中的神经胶质细胞而不是感觉神经元命运决定的关键调节因子。然而， Sox10 在谱系分离过程中调节神经胶质细胞命运决定的机制仍知之甚少。在我们的研究中，我们表明神经发生决定因子 Neurogenin 2 (Neurog2) 在禽类主干 NC 祖细胞中与 Sox10 表现出短暂的重叠表达，这些细胞在向形成的 DRG 迁移过程中逐渐经历谱系分离。获得和丧失功能研究表明，Neurog2 的短暂表达是由于 Sox10 调节其蛋白稳定性。转录谱分析确定了 Sox10 调节的 F-box 仅蛋白 (Fbxo9)，它是一种 Skp1-Cul-F-box 型泛素连接酶，作用于 Neurog2。一致地，在 NC 祖细胞中过表达 Fbxo9 通过泛素化下调 Neurog2 蛋白表达并促进神经胶质谱系，而牺牲神经元分化，而 Fbxo9 敲低则产生相反的现象。从机制上讲，我们发现 Fbxo9 与 Neurog2 相互作用，通过 F-box 基序促进其不稳定。最后，上位性分析进一步表明，Fbxo9 和可能其他 F-box 成员介导了 Sox10 在不稳定 Neurog2 蛋白和指导 NC 祖细胞谱系向神经胶质细胞而不是感觉神经元方向的作用。总之，这些发现揭示了 Sox10-Fbxo9 调节轴通过 Neurog2 不稳定促进 NC 祖细胞的神经胶质命运。
