Wang Ke, Liu Xing-Yang, Liu Sui-Feng, Wang Xiao-Xia, Wei Yi-Hua, Zhu Jun-Rong, Liu Jing, Xu Xiu Qin, Wen Lei
Institute of Stem Cell and Regenerative Medicine, Women and Children's Hospital of Xiamen University, Fujian Provincial Key Laboratory of Neurodegenerative Disease and Aging Research, State Key Laboratory of Cellular Stress Biology, School of Medicine, Xiamen University, Xiamen, Fujian 361000, China.
Center for Brain Sciences, Department of Traditional Chinese Medicine, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian 361000, China.
Theranostics. 2024 Aug 1;14(11):4499-4518. doi: 10.7150/thno.96045. eCollection 2024.
Adult neurogenesis in the subventricular zone (SVZ) is essential for maintaining neural homeostasis, and its dysregulation contributes to anosmia and delayed tissue healing in neurological disorders, such as Parkinson's disease (PD). Despite intricate regulatory networks identified in SVZ neurogenesis, the molecular mechanisms dynamically maintaining neural stem/progenitor cells (NSPCs) in response to physiological and pathological stimuli remain incompletely elucidated. We generated an RNA binding motif protein 24 (Rbm24) knockout model to investigate its impact on adult neurogenesis in the SVZ, employing immunofluorescence, immunoblot, electrophysiology, RNA-sequencing, and experiments. Further investigations utilized a PD mouse model, along with genetic and pharmacological manipulations, to elucidate Rbm24 involvement in PD pathology. Rbm24, a multifaceted post-transcriptional regulator of cellular homeostasis, exhibited broad expression in the SVZ from development to aging. Deletion of Rbm24 significantly impaired NSPC proliferation in the adult SVZ, ultimately resulting in collapsed neurogenesis in the olfactory bulb. Notably, Rbm24 played a specific role in maintaining Notch1 mRNA stability in adult NSPCs. The Rbm24/Notch1 signaling axis was significantly downregulated in the SVZ of PD mice. Remarkably, overexpression of Rbm24 rescued disruption of adult neurogenesis and olfactory dysfunction in PD mice, and these effects were hindered by DAPT, a potent inhibitor of Notch1. Our findings highlight the critical role of the Rbm24/Notch1 signaling axis in regulating adult SVZ neurogenesis under physiological and pathological circumstances. This provides valuable insights into the dynamic regulation of NSPC homeostasis and offers a potential targeted intervention for PD and related neurological disorders.
脑室下区（SVZ）的成体神经发生对于维持神经内环境稳定至关重要，其失调会导致嗅觉丧失以及帕金森病（PD）等神经系统疾病中组织愈合延迟。尽管在SVZ神经发生中已确定了复杂的调控网络，但响应生理和病理刺激动态维持神经干/祖细胞（NSPCs）的分子机制仍未完全阐明。我们构建了RNA结合基序蛋白24（Rbm24）基因敲除模型，采用免疫荧光、免疫印迹、电生理学、RNA测序等实验来研究其对SVZ成体神经发生的影响。进一步的研究利用PD小鼠模型以及基因和药物操作，以阐明Rbm24在PD病理过程中的作用。Rbm24是细胞内环境稳定的多方面转录后调节因子，从发育到衰老在SVZ中均有广泛表达。Rbm24的缺失显著损害了成年SVZ中NSPC的增殖，最终导致嗅球中的神经发生崩溃。值得注意的是，Rbm24在维持成年NSPCs中Notch1 mRNA稳定性方面发挥了特定作用。在PD小鼠的SVZ中，Rbm24/Notch1信号轴显著下调。值得注意的是，Rbm24的过表达挽救了PD小鼠成体神经发生的破坏和嗅觉功能障碍，而这些作用被Notch1的强效抑制剂DAPT所阻断。我们的研究结果突出了Rbm24/Notch1信号轴在生理和病理情况下调节成年SVZ神经发生中的关键作用。这为NSPC内环境稳定的动态调节提供了有价值的见解，并为PD及相关神经系统疾病提供了潜在的靶向干预措施。
