Abstract
Dysfunctions of neural stem cells (NSCs) often lead to a variety of neurological diseases. Thus, therapies based on NSCs have gained increasing attention recently. It has been documented that microRNA (miR)-421 represses the autophagy and apoptosis of mouse hippocampal neurons and confers a role in the repair of ischemic brain injury (IBI). Herein, we aimed to illustrate the effects of miR-421 on NSC self-renewal. The downstream factors of miR-421 were predicted initially, followed by gain- and loss-of-function assays to examine their effects on NSC self-renewal. Immunoprecipitation and dual luciferase assays were conducted to validate the interaction among miR-421, PTEN-induced putative kinase 1 (PINK1), HDAC3, and forkhead box O3 (FOXO3). A mouse model with IBI was developed to substantiate the impact of the miR-421/PINK1/HDAC3/FOXO3 axis on NSC self-renewal. The expression of miR-421 was downregulated during differentiation of human embryonic NSCs, and miR-421 overexpression accelerated NSC self-renewal. Besides, miR-421 targeted PINK1 and restricted its expression in NSCs and further suppressed HDAC3 phosphorylation and enhanced FOXO3 acetylation. In conclusion, our data elucidated that miR-421 overexpression may facilitate NSC self-renewal through the PINK1/HDAC3/FOXO3 axis, which may provide potential therapeutic targets for the development of novel therapies for IBI.
Highlights
MATERIALS AND METHODSDespite intensive research for many years, management for disorders of the nervous system, including ischemic brain injury (IBI), trauma-induced nerve injuries, and neurodegenerative diseases, remains poorly developed (Ma et al, 2018)
PTEN-induced putative kinase 1 (PINK1) deficiency may lead to defects in GFAP-positive astrogliogenesis involved in brain development and neural stem cells (NSCs) differentiation (Choi et al, 2016a)
MiR-421 overexpression blocked the apoptosis and autophagy of hippocampal neurons in the increased the expression of marker genes (MSI1, HES1, and BMI1) of NSCs and proliferation-related gene MKI67
Summary
MATERIALS AND METHODSDespite intensive research for many years, management for disorders of the nervous system, including ischemic brain injury (IBI), trauma-induced nerve injuries, and neurodegenerative diseases, remains poorly developed (Ma et al, 2018). It is urgent to investigate the molecular mechanism underlying NSC renewal in order to facilitate the development of NSC-based therapeutic regimens for the treatment of nervous system diseases. Evidence exists supporting that microRNA (miR)-421 is highly expressed in the amygdala and shows the potential for affecting the repair after brain injury (Yang et al, 2014). We speculate that miR-421 may play a role in the self-renewal of NSCs. miR-421 can target and inhibit PTEN-induced putative kinase 1 (PINK1) (Wang et al, 2015), and PINK1 was identified as a differentially expressed gene in our prediction analysis. MiR-421 may affect the renewal and differentiation of NSCs by regulating PINK1 expression
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