Clinical Neuroscience Institute, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China; Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA.
Clinical Neuroscience Institute, The First Affiliated Hospital of Jinan University, Guangzhou 510630, China; Department of Neurology, The First Clinical Medical School of Jinan University, Guangzhou, China.
J Adv Res. 2023 Sep;51:73-90. doi: 10.1016/j.jare.2022.11.007. Epub 2022 Nov 17.
Spontaneous recovery after CNS injury is often very limited and incomplete, leaving most stroke patients with permanent disability. Maf1 is known as a key growth suppressor in proliferating cells. However, its role in neuronal cells after stroke remains unclear.
We aimed to investigate the mechanistic role of Maf1 in spontaneous neural repair and evaluated the therapeutic effect of targeting Maf1 on stroke recovery.
We used mouse primary neurons to determine the signaling mechanism of Maf1, and the cleavage-under-targets-and-tagmentation-sequencing to map the whole-genome promoter binding sites of Maf1 in isolated mature cortical neurons. Photothrombotic stroke model was used to determine the therapeutic effect on neural repair and functional recovery by AAV-mediated Maf1 knockdown.
We found that Maf1 mediates mTOR signaling to regulate RNA polymerase III (Pol III)-dependent rRNA and tRNA transcription in mouse cortical neurons. mTOR regulates neuronal Maf1 phosphorylation and subcellular localization. Maf1 knockdown significantly increases Pol III transcription, neurite outgrowth and dendritic spine formation in neurons. Conversely, Maf1 overexpression suppresses such activities. In response to photothrombotic stroke in mice, Maf1 expression is increased and accumulates in the nucleus of neurons in the peripheral region of infarcted cortex, which is the key region for neural remodeling and repair during spontaneous recovery. Intriguingly, Maf1 knockdown in the peri-infarct cortex significantly enhances neural plasticity and functional recovery. Mechanistically, Maf1 not only interacts with the promoters and represses Pol III-transcribed genes, but also those of CREB-associated genes that are critical for promoting plasticity during neurodevelopment and neural repair.
These findings indicate Maf1 as an intrinsic neural repair suppressor against regenerative capability of mature CNS neurons, and suggest that Maf1 is a potential therapeutic target for enhancing functional recovery after ischemic stroke and other CNS injuries.
中枢神经系统损伤后的自发恢复通常非常有限且不完全，这使得大多数中风患者留有永久性残疾。Maf1 被认为是增殖细胞中的关键生长抑制因子。然而，其在中风后神经元细胞中的作用仍不清楚。
我们旨在研究 Maf1 在自发神经修复中的机制作用，并评估靶向 Maf1 对中风恢复的治疗效果。
我们使用小鼠原代神经元来确定 Maf1 的信号机制，并通过靶向和标签测序来绘制分离成熟皮质神经元中 Maf1 的全基因组启动子结合位点图谱。光血栓性中风模型用于通过 AAV 介导的 Maf1 敲低确定对神经修复和功能恢复的治疗效果。
我们发现 Maf1 介导 mTOR 信号通路调节 RNA 聚合酶 III（Pol III）依赖性 rRNA 和 tRNA 转录，在小鼠皮质神经元中。mTOR 调节神经元 Maf1 的磷酸化和亚细胞定位。Maf1 敲低可显著增加神经元中的 Pol III 转录、轴突生长和树突棘形成。相反，Maf1 过表达会抑制这些活动。在小鼠光血栓性中风中，Maf1 表达增加并在梗死皮质外周区神经元核内积累，这是自发恢复期间神经重塑和修复的关键区域。有趣的是，Maf1 在梗死周边皮质中的敲低显著增强了神经可塑性和功能恢复。机制上，Maf1 不仅与启动子相互作用并抑制 Pol III 转录基因，还与 CREB 相关基因相互作用，这些基因对于促进神经发育和神经修复期间的可塑性至关重要。
这些发现表明 Maf1 作为一种内在的神经修复抑制因子，对抗成熟中枢神经系统神经元的再生能力，并表明 Maf1 是增强缺血性中风和其他中枢神经系统损伤后功能恢复的潜在治疗靶点。
