Dataset Information

PI3K/AKT/mTOR Signaling Mediates Valproic Acid-Induced Neuronal Differentiation of Neural Stem Cells through Epigenetic Modifications.

ABSTRACT: Although valproic acid (VPA), has been shown to induce neuronal differentiation of neural stem cells (NSCs), the underlying mechanisms remain poorly understood. Here we investigated if and how mammalian target of rapamycin (mTOR) signaling is involved in the neuronal differentiation of VPA-induced NSCs. Our data demonstrated that mTOR activation not only promoted but also was necessary for the neuronal differentiation of NSCs induced by VPA. We further found that inhibition of mTOR signaling blocked demethylation of neuron-specific gene neurogenin 1 (Ngn1) regulatory element in induced cells. These are correlated with the significant alterations of passive DNA demethylation and the active DNA demethylation pathway in the Ngn1 promoter, but not the suppression of lysine-specific histone methylation and acetylation in the promoter region of Ngn1. These findings highlight a potentially important role for mTOR signaling, by working together with DNA demethylation, to influence the fate of NSCs via regulating the expression of Ngn1 in VPA-induced neuronal differentiation of NSCs.

SUBMITTER: Zhang X

PROVIDER: S-EPMC5425725 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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PI3K/AKT/mTOR Signaling Mediates Valproic Acid-Induced Neuronal Differentiation of Neural Stem Cells through Epigenetic Modifications.

Zhang Xi X He Xiaosong X Li Qingqing Q Kong Xuejian X Ou Zhenri Z Zhang Le L Gong Zhuo Z Long Dahong D Li Jianhua J Zhang Meng M Ji Weidong W Zhang Wenjuan W Xu Liping L Xuan Aiguo A

Stem cell reports 20170501 5

Although valproic acid (VPA), has been shown to induce neuronal differentiation of neural stem cells (NSCs), the underlying mechanisms remain poorly understood. Here we investigated if and how mammalian target of rapamycin (mTOR) signaling is involved in the neuronal differentiation of VPA-induced NSCs. Our data demonstrated that mTOR activation not only promoted but also was necessary for the neuronal differentiation of NSCs induced by VPA. We further found that inhibition of mTOR signaling blo ...[more]

PMID: 28494938

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Project description:FeHV-1 is the causative agent of infectious rhinotracheitis in cats. The relationship between viral infection and the PI3K/Akt/mTOR pathway, as well as its function in crucial physiological processes like as autophagy, apoptosis or the IFN induction cascade is known for other varicelloviruses. However, there is no information on whether autophagy is activated during FeHV-1 infection nor on how this infection modifies PI3K/Akt/mTOR pathway. In this work, we aim to elucidate the involvement of this pathway during cytolytic infection by FeHV-1 in permissive cell lines. Using a phenotypic approach, the expression of proteins involved in the PI3K/Akt/mTOR pathway was examined by Western blot analysis. The findings demonstrated the lack of modifications in relation to viral dose (except for phospho-mTOR), whereas there were changes in the expression of several markers in relation to time as well as a mismatch in the time of activation of this axis. These results suggest that FeHV-1 may interact independently with different autophagic signaling pathways. In addition, we found an early phosphorylation of Akt, approximately 3 h after infection, without a concomitant decrease in constitutive Akt. This result suggests a possible role for this axis in viral entry. In a second phase, the use of early autophagy inhibitors was examined for viral yield, cytotoxic effects, viral glycoprotein expression, and autophagy markers and resulted in inefficient inhibition of viral replication (12 h post-infection for LY294002 and 48 h post-infection for 3-methyladenine). The same markers were examined during Akt knockdown, and we observed no differences in viral replication. This result could be explained by the presence of a protein kinase in the FeHV-1 genome (encoded by the Us3 gene) that can phosphorylate various Akt substrates as an Akt surrogate, as has already been demonstrated in genetically related viruses (HSV-1, PRV, etc.). For the same reasons, the use of LY294002 at the beginning of infection did not affect FeHV-1-mediated Akt phosphorylation. Our findings highlight changes in the PI3K/Akt/mTOR pathway during FeHV-1 infection, although further research is needed to understand the importance of these changes and how they affect cellular processes and viral propagation.

Dataset Information

PI3K/AKT/mTOR Signaling Mediates Valproic Acid-Induced Neuronal Differentiation of Neural Stem Cells through Epigenetic Modifications.

Publications

PI3K/AKT/mTOR Signaling Mediates Valproic Acid-Induced Neuronal Differentiation of Neural Stem Cells through Epigenetic Modifications.

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