PDF(Pubmed)
Abstract：
Rationale: 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. Methods: 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 in vitro experiments. Further investigations utilized a PD mouse model, along with genetic and pharmacological manipulations, to elucidate Rbm24 involvement in PD pathology. Results: 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. Conclusions: 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.
摘要：
原理：脑室下区（SVZ）的成人神经发生对于维持神经稳态至关重要，它的失调会导致神经系统疾病的失语症和组织愈合延迟，如帕金森病（PD）。尽管在SVZ神经发生中发现了复杂的调节网络，动态维持神经干/祖细胞（NSPCs）响应生理和病理刺激的分子机制仍未完全阐明。方法：我们建立了一个RNA结合基序蛋白24（Rbm24）敲除模型，以研究其对SVZ中成人神经发生的影响。采用免疫荧光，免疫印迹,电生理学,RNA测序，和体外实验。进一步的研究利用PD小鼠模型，连同遗传和药理操作，阐明Rbm24参与PD病理。结果：Rbm24，细胞稳态的多方面转录后调节因子，从发育到衰老在SVZ中表现出广泛的表达。Rbm24的缺失显着损害成年SVZ的NSPC增殖，最终导致嗅球神经发生塌陷。值得注意的是,Rbm24在维持成年NSPCs中Notch1mRNA的稳定性中起着特定的作用。Rbm24/Notch1信号轴在PD小鼠的SVZ中显著下调。值得注意的是,Rbm24的过表达拯救了PD小鼠成年神经发生和嗅觉功能障碍的破坏，这些影响受到DAPT的阻碍，Notch1的有效抑制剂。结论：我们的发现强调了Rbm24/Notch1信号轴在生理和病理情况下调节成人SVZ神经发生的关键作用。这为NSPC稳态的动态调节提供了有价值的见解，并为PD和相关神经系统疾病提供了潜在的针对性干预措施。
