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

Abstract

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 G0/G1 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 p27KIP1 and p57KIP2 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 p27KIP1 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.

Knockdown of hsa_circ_0001275 reverses dexamethasone-induced osteoblast growth inhibition via mediation of miR-377/CDKN1B axis

“…CDKN1B has been reported to regulate G 1 progression and maintain the cell function in response to cell proliferation inhibition or cell differentiation [36,37]. In addition, it has been confirmed that CDKN1B can act as a key modulator in cell growth by induction of CDK2 and Cyclin E1 [38,39]. The findings were consistent to these of previous studies.…”

Melatonin promotes cell cycle progression of neural stem cells subjected to manganese via Nurr1

“…37 Particularly, it is pointed out that the inhibition of the activity of Cyclin-CDK complexes in vitro and the blocking of the cell cycle process by regulating the G 1 to S phase transition are all closely related to p57 KIP2 . 22 Our results showed that there was a notable rise in negative cell cycle regulatory factors, specifically p27 KIP1 and p57 KIP2 , for 24 h after treatment with Mn. More importantly, Nurr1 is considered to be a neuroprotective transcription regulator, which is closely related to the cell cycle.…”

Nurr1 Is Not an Essential Regulator of BDNF in Mouse Cortical Neurons

“…First, Nurr1 activation by AQ has been linked to neuroprotection. Activation of Nurr1 by AQ leads to the generation of neurons from cortical [ 42 ] and hippocampal [ 42 , 47 , 48 ] neural precursor cells, enhances short-and long-term memory, and improves cognitive deficits in mouse models of Parkinson’s [ 49 , 50 ] and Alzheimer’s disease [ 51 ]. Second, AQ is known to be a selective agonist for Nurr1 with no effect on other members of the NR4A family (Nur77 and NOR1) [ 49 ].…”