Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines, La Jolla, CA 92037, USA; Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines, La Jolla, CA 92037, USA.
Cell Rep. 2023 Nov 28;42(11):113282. doi: 10.1016/j.celrep.2023.113282. Epub 2023 Oct 28.
Schwann cells respond to acute axon damage by transiently transdifferentiating into specialized repair cells that restore sensorimotor function. However, the molecular systems controlling repair cell formation and function are not well defined, and consequently, it is unclear whether this form of cellular plasticity has a role in peripheral neuropathies. Here, we identify Mitf as a transcriptional sensor of axon damage under the control of Nrg-ErbB-PI3K-PI5K-mTorc2 signaling. Mitf regulates a core transcriptional program for generating functional repair Schwann cells following injury and during peripheral neuropathies caused by CMT4J and CMT4D. In the absence of Mitf, core genes for epithelial-to-mesenchymal transition, metabolism, and dedifferentiation are misexpressed, and nerve repair is disrupted. Our findings demonstrate that Schwann cells monitor axonal health using a phosphoinositide signaling system that controls Mitf nuclear localization, which is critical for activating cellular plasticity and counteracting neural disease.
许旺细胞对急性轴突损伤的反应是短暂地向专门的修复细胞转化，以恢复感觉运动功能。然而，控制修复细胞形成和功能的分子系统还没有很好地定义，因此，尚不清楚这种细胞可塑性是否在外周神经病变中起作用。在这里，我们确定 Mitf 是轴突损伤的转录传感器，受 Nrg-ErbB-PI3K-PI5K-mTorc2 信号的控制。Mitf 调节了一个核心转录程序，用于在损伤后和 CMT4J 和 CMT4D 引起的周围神经病变期间产生功能性修复许旺细胞。在没有 Mitf 的情况下，上皮到间充质转化、代谢和去分化的核心基因表达错误，神经修复被破坏。我们的发现表明，许旺细胞使用一种磷酸肌醇信号系统来监测轴突的健康状况，该系统控制 Mitf 的核定位，这对于激活细胞可塑性和对抗神经疾病至关重要。
