Theranostics
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2024
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IF 12.4
Ke Wang,Xing-Yang Liu,Sui-Feng Liu,Xiao-Xia Wang,Yi-Hua Wei,Jun-Rong Zhu,Jing Liu,Xiu Qin Xu,Lei Wen
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.
研究领域:
神经科学
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分子生物学
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神经退行性疾病
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干细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CARDIOVASCULAR RESEARCH
·
2025
·
IF 13.3
Zhang Huawei,Liu Jing,Sun Daqian,Liu Yuxiu,Sun Wenhao,Wang Shanshan,Xu Xiuqin
AimsVascular remodeling plays a crucial role in the pathogenesis of vascular diseases. Our previous research highlighted the significance of RNA-binding protein 24 (RBM24) in the pathogenesis of dilated cardiomyopathy and the development of the zebrafish circulatory system. However, the specific role of RBM24 in vascular remodeling and its underlying mechanisms remain unclear. This study aims to elucidate the role of RBM24 in vascular remodeling and explore its associated signaling pathways as potential therapeutic targets.Methods and ResultsWe established human (in vitro) and mouse (in vivo) vascular injury models to identify the regulatory role of RBM24 in vascular smooth muscle cell (VSMC) phenotypic switching and vascular remodeling. mRNA stability assays, RNA immunoprecipitation (RIP), and luciferase reporter assays were employed to explore the underlying mechanisms. RBM24 was significantly upregulated in injured mouse carotid arteries and platelet-derived growth factor (PDGF)-stimulated human VSMCs. VSMC-specific knockout of Rbm24 in mice attenuated injury-induced vascular remodeling, evidenced by reduced neointima formation, increased contractile markers and decreased synthetic and proliferative markers. Conversely, AAV-mediated RBM24 overexpression promoted vascular remodeling. Further, the silencing of RBM24 in human VSMCs suppressed VSMC phenotypic switching, as indicated by reduced proliferation and migration, increased expression of contractile markers, and decreased synthetic and proliferative markers, whereas RBM24 overexpression had the opposite effect. Mechanistically, RBM24 stabilized Janus kinase 2 (JAK2) mRNA, promoting its translation and enhancing the JAK2-Signal transducer and activator of transcription 3 (STAT3)- Krüppel-like factor 4 (KLF4) signaling axis to drive VSMC phenotypic switching and vascular remodeling. Furthermore, STAT3 inhibition via shRNA or Nifuroxazide effectively suppressed VSMC phenotypic switching and injury-induced vascular remodeling.ConclusionsThis study demonstrates that RBM24 promotes vascular remodeling by stabilizing JAK2 mRNA and enhancing the JAK2-STAT3-KLF4 signaling axis. Targeting RBM24 and its associated pathways may offer novel therapeutic strategies against vascular remodeling.
✓ 已验证
DOI
高影响因子
RNA Biology
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2020
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IF 5.35
Longqing Zheng,Huijun Yuan,Mengkai Zhang,Cuicui Wang,Xuemin Cai,Jing Liu,Xiu Qin Xu
Tissue-specific alternative splicing (AS) is emerging as one of the most exciting types of mechanisms associated with organ development and disease. In the auditory system, many hearing-related genes undergo AS, and errors in this process result in syndromic or non-syndromic hearing loss. However, little is known about the factors and mechanisms directing AS in the inner ear. In the present study, we identified a novel RNA-binding protein, Rbm24, which was critically involved in regulating inner-ear-specific AS. Rbm24 deletion resulted in hearing loss and defects in motor coordination. Global splicing analysis showed Rbm24 was required for correct splicing of a subset of pre-mRNA transcripts with essential roles in stereocilia integrity and survival of hair cells. Furthermore, we identified that Rbm24 directly regulated the splicing of Cdh23, a known disease gene responsible for human Usher syndrome 1D and non-syndromic autosomal recessive deafness DFNB12. In conclusion, our findings demonstrated that Rbm24 was a critical factor in regulating inner-ear-specific splicing and maintaining the hearing and motor coordination function of the inner ear. Our data not only offer mechanistic insights but also provide functional annotation of Rbm24 splicing targets that contribute to hearing loss.
研究领域:
分子生物学
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遗传学
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神经科学
✓ 已验证
DOI
PubMed
高影响因子
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