Pharmacological Stimulation of Nurr1 Promotes Cell Cycle Progression in Adult Hippocampal Neural Stem Cells

• Published in: International journal of molecular sciences 2019-12, Vol.21 (1), p.4
• Main Authors: Moon, Haena, Jeon, Seong Gak, Kim, Jin-Il, Kim, Hyeon Soo, Lee, Sangho, Kim, Dongok, Park, Seungjoon, Moon, Minho, Chung, Hyunju
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; Adult Stem Cells - drug effects; Adult Stem Cells - metabolism; Alzheimer's disease; Amodiaquine; Amodiaquine - pharmacology; Animals; Biomarkers; Cell cycle; Cell Cycle - drug effects; Cell Cycle - genetics; Cell growth; Cell Proliferation; Cyclin A; Cyclin-dependent kinase; Cyclin-dependent kinase 2; Cyclin-dependent kinase inhibitor p27; Cyclin-dependent kinases; Dentate gyrus; Dentate Gyrus - metabolism; E2F1 Transcription Factor - genetics; E2F1 Transcription Factor - metabolism; Flow cytometry; Fluorescence; Gene Expression Regulation; Hippocampus; Hippocampus - cytology; Humans; Immunohistochemistry; Kinases; Male; Markers; Memory; Memory tasks; Mice; Neural stem cells; Neural Stem Cells - drug effects; Neural Stem Cells - metabolism; Neurogenesis; Neurogenesis - drug effects; Neurogenesis - genetics; Nuclear Receptor Subfamily 4, Group A, Member 2 - genetics; Nuclear Receptor Subfamily 4, Group A, Member 2 - metabolism; Nuclear receptors; Nurr1 protein; Parkinson's disease; Pharmacology; Proliferating cell nuclear antigen; Proteins; Rats; Regulation; Rodents; S phase; Spatial analysis; Spatial memory; Stem cell transplantation; Stem cells; Stimulation; Transcription factors
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21010004

Nuclear receptor related-1 (Nurr1) protein performs a crucial role in hippocampal neural stem cell (hNSC) development as well as cognitive functions. We previously demonstrated that the pharmacological stimulation of Nurr1 by amodiaquine (AQ) promotes spatial memory by enhancing adult hippocampal neurogenesis. However, the role of Nurr1 in the cell cycle regulation of the adult hippocampus has not been investigated. This study aimed to examine changes in the cell cycle-related molecules involved in adult hippocampal neurogenesis induced by Nurr1 pharmacological stimulation. Fluorescence-activated cell sorting (FACS) analysis showed that AQ improved the progression of cell cycle from G /G to S phase in a dose-dependent manner, and MEK1 or PI3K inhibitors attenuated this progression. In addition, AQ treatment increased the expression of cell proliferation markers MCM5 and PCNA, and transcription factor E2F1. Furthermore, pharmacological stimulation of Nurr1 by AQ increased the expression levels of positive cell cycle regulators such as cyclin A and cyclin-dependent kinases (CDK) 2. In contrast, levels of CDK inhibitors p27 and p57 were reduced upon treatment with AQ. Similar to the in vitro results, RT-qPCR analysis of AQ-administered mice brains revealed an increase in the levels of markers of cell cycle progression, PCNA, MCM5, and Cdc25a. Finally, AQ administration resulted in decreased p27 and increased CDK2 levels in the dentate gyrus of the mouse hippocampus, as quantified immunohistochemically. Our results demonstrate that the pharmacological stimulation of Nurr1 in adult hNSCs by AQ promotes the cell cycle by modulating cell cycle-related molecules.