Perfluorooctane sulfonate (PFOS) impairs the proliferation of C17.2 neural stem cells via the downregulation of GSK-3β/β-catenin signaling.

The neurotoxic effects of perfluorooctane sulfonate (PFOS) have attracted significant research attention in recent years. In the present study, we investigated the impact of PFOS exposure on the physiology of neural stem cells (NSCs) in vitro. We showed that PFOS exposure markedly attenuated the proliferation of C17.2 neural stem cells in both dose- and time-dependent manners. Additionally, we found that PFOS decreased Ser9 phosphorylation of glycogen synthase kinase-3β (pSer9-GSK-3β), leading to the activation of GSK-3β and resultant downregulation of cellular β-catenin. Furthermore, blockage of GSK-3β with lithium chloride significantly attenuated both the PFOS-induced downregulation of GSK-3β/β-catenin and the proliferative impairment of C17.2 cells. Notably, the expression of various downstream targets was altered accordingly, such as c-myc, cyclin D1 and survivin. In conclusion, the present study demonstrated that PFOS decreased the proliferation of C17.2 cells via the negative modulation of the GSK-3β/β-catenin pathway. We present the potential mechanisms underlying the PFOS-induced toxic effects on NSCs to provide novel insights into the neurotoxic mechanism of PFOS. Copyright © 2016 John Wiley & Sons, Ltd.

Dong X ，Yang J ，Nie X ，Xiao J ，Jiang S ... -  《-》

The downregulation of Wnt/β-catenin signaling pathway is associated with zinc deficiency-induced proliferative deficit of C17.2 neural stem cells.

Zinc is an essential nutrient that is important for normal brain development. Zinc deficiency has been linked to aberrant neurological development and functioning. However, the molecular mechanisms underlying Zinc deficiency-induced neurological disorders remain largely elusive. In the present study, we showed that the proliferation of C17.2 neural stem cells (NSCs) was evidently impaired after exposed to low levels of Zinc chelator, N,N,N',N'-tetrakis-(2-pyridylmethy) ethylenediamine (TPEN). In addition, we found that TPEN-induced proliferative deficit of NSCs was related with significant downregulation of Wnt/β-catenin signaling. Zinc deficiency impaired the proliferation of neural stem cells in dose- and time-dependent manners. Western blot revealed that the levels of p-Ser9-glycogensynthase kinase-3β (p-GSK-3β) and β-catenin were remarkably downregulated during TPEN-induced C17.2 proliferative impairment. Moreover, immunofluorescent analysis indicated that the level of nuclear β-catenin was apparently decreased following TPEN exposure. Furthermore, application with GSK-3β inhibitor lithium chloride (LiCl) reversed TPEN-induced downregulation of β-catenin and impairment of cell proliferation. Flow cytometry analysis also showed that TPEN-induced impairment of NSC proliferation could be reversed by LiCl. Taken together, these findings suggested that the disturbance of canonical Wnt/β-catenin signaling pathway partially accounted for Zinc deficiency-induced proliferative impairment of NSCs.

Zhao J ，Han J ，Jiang J ，Shi S ，Ma X ，Liu X ，Wang C ，Nie X ，He Y ，Jiang S ，Wan C ... -  《-》

Perfluorooctane sulfonate induces neuronal and oligodendrocytic differentiation in neural stem cells and alters the expression of PPARγ in vitro and in vivo.

Perfluorinated compounds are ubiquitous chemicals of major concern for their potential adverse effects on the human population. We have used primary rat embryonic neural stem cells (NSCs) to study the effects of perfluorooctane sulfonate (PFOS) on the process of NSC spontaneous differentiation. Upon removal of basic fibroblast growth factor, NSCs were exposed to nanomolar concentrations of PFOS for 48 h, and then allowed to differentiate for additional 5 days. Exposure to 25 or 50 nM concentration resulted in a lower number of proliferating cells and a higher number of neurite-bearing TuJ1-positive cells, indicating an increase in neuronal differentiation. Exposure to 50 nM also significantly increased the number of CNPase-positive cells, pointing to facilitation of oligodendrocytic differentiation. PPAR genes have been shown to be involved in PFOS toxicity. By q-PCR we detected an upregulation of PPARγ with no changes in PPARα or PPARδ genes. One of the downstream targets of PPARs, the mitochondrial uncoupling protein 2 (UCP2) was also upregulated. The number of TuJ1- and CNPase-positive cells increased after exposure to PPARγ agonist rosiglitazone (RGZ, 3 μM) and decreased after pre-incubation with the PPARγ antagonist GW9662 (5 μM). RGZ also upregulated the expression of PPARγ and UCP2 genes. Meanwhile GW9662 abolished the UCP2 upregulation and decreased Ca²⁺ activity induced by PFOS. Interestingly, a significantly higher expression of PPARγ and UCP3 genes was also detected in mouse neonatal brain after prenatal exposure to PFOS. These data suggest that PPARγ plays a role in the alteration of spontaneous differentiation of NSCs induced by nanomolar concentrations of PFOS.

Wan Ibrahim WN ，Tofighi R ，Onishchenko N ，Rebellato P ，Bose R ，Uhlén P ，Ceccatelli S ... -  《-》

BDNF promotes human neural stem cell growth via GSK-3β-mediated crosstalk with the wnt/β-catenin signaling pathway.

Yang JW ，Ma W ，Luo T ，Wang DY ，Lu JJ ，Li XT ，Wang TT ，Cheng JR ，Ru J ，Gao Y ，Liu J ，Liang Z ，Yang ZY ，Dai P ，He YS ，Guo XB ，Guo JH ，Li LY ... -  《-》

Claulansine F promoted the neuronal differentiation of neural stem and progenitor cells through Akt/GSK-3β/β-catenin pathway.

The persistence of neurogenesis raises the idea that neurons produced by the resident or transplanted neural stem cells could replace the neurons lost from brain injury or neurodegenerative disease. Therefore, compounds or methods for promoting neuronal differentiation become the focus of neurodegenerative disease therapy research. Claulansine F (Clau F), a newly discovered carbazole alkaloid, has been showed to induce neuritogenesis in PC12 cells. Herein, we studied the effect of Clau F on neuronal differentiation of neural stem/progenitor cells (NS/PCs). The current study demonstrated that Clau F initiated neuronal differentiation with a significant increase of TuJ1-positive cells and TuJ1 protein levels. We also found that Clau F promoted the maturity and sustainability of neurons by increasing MAP2-positive cells and MAP2 protein levels. At the same time, Clau F significantly inhibited the proliferation of NS/PCs. The underlying mechanism of Clau F was preliminary explored. Clau F treatment resulted in a profound increase of phosphorylation of Akt and GSK-3β, which led to GSK-3β inhibition and subsequently the nuclear accumulation of β-catenin. Further, the interaction between β-catenin and p300 in the nucleus was enhanced and the transcription of p300/β-catenin responsive genes were increased significantly (c-jun, fra-1) by Clau F. Importantly, the positive effect of Clau F on neuronal differentiation was abolished by Akti-1/2, a specific inhibitor of Akt-1/2 kinase, which indicated the involvement of Akt/GSK-3β in Clau F-mediated neuronal differentiation. In conclusion, these data suggested that Clau F promoted neuronal differentiation through Akt/GSK-3β/β-catenin signaling pathway in NS/PCs.

Huang JY ，Ma YZ ，Yuan YH ，Zuo W ，Chu SF ，Liu H ，Du GH ，Zhang DM ，Chen NH ... -  《-》