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GDF11 induces differentiation and apoptosis and inhibits migration of C17.2 neural stem cells via modulating MAPK signaling pathway.

ABSTRACT: GDF11, a member of TGF-? superfamily, has recently received widespread attention as a novel anti-ageing/rejuvenation factor to reverse age-related dysfunctions in heart and skeletal muscle, and to induce angiogenesis and neurogenesis. However, these positive effects of GDF11 were challenged by several other studies. Furthermore, the mechanism is still not well understood. In the present study, we evaluated the effects of GDF11 on C17.2 neural stem cells. GDF11 induced differentiation and apoptosis, and suppressed migration of C17.2 neural stem cells. In addition, GDF11 slightly increased cell viability after 24 h treatment, showed no effects on proliferation for about 10 days of cultivation, and slightly decreased cumulative population doubling for long-term treatment (p < 0.05). Phospho-proteome profiling array displayed that GDF11 significantly increased the phosphorylation of 13 serine/threonine kinases (p < 0.01), including p-p38, p-ERK and p-Akt, in C17.2 cells, which implied the activation of MAPK pathway. Western blot validated that the results of phospho-proteome profiling array were reliable. Based on functional analysis, we demonstrated that the differentially expressed proteins were mainly involved in signal transduction which was implicated in cellular behavior. Collectively, our findings suggest that, for neurogenesis, GDF11 might not be the desired rejuvenation factor, but a potential target for pharmacological blockade.

SUBMITTER: Wang Z

PROVIDER: S-EPMC6128255 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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GDF11 induces differentiation and apoptosis and inhibits migration of C17.2 neural stem cells via modulating MAPK signaling pathway.

Wang Zongkui Z Dou Miaomiao M Liu Fengjuan F Jiang Peng P Ye Shengliang S Ma Li L Cao Haijun H Du Xi X Sun Pan P Su Na N Lin Fangzhao F Zhang Rong R Li Changqing C

PeerJ 20180904

GDF11, a member of TGF-β superfamily, has recently received widespread attention as a novel anti-ageing/rejuvenation factor to reverse age-related dysfunctions in heart and skeletal muscle, and to induce angiogenesis and neurogenesis. However, these positive effects of GDF11 were challenged by several other studies. Furthermore, the mechanism is still not well understood. In the present study, we evaluated the effects of GDF11 on C17.2 neural stem cells. GDF11 induced differentiation and apoptos ...[more]

PMID: 30202652

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Project description:Most studies of IR effects on neural cells and tissues in the brain are still focused on loss of neural stem cells. On the other hand, the effects of IR on neuronal differentiation and its implication in IR-induced brain damage are not well defined. To investigate the effects of IR on C17.2 mouse neural stem-like cells and mouse primary neural stem cells, neurite outgrowth and expression of neuronal markers and neuronal function-related genes were examined. To understand this process, the signaling pathways including PI3K, STAT3, metabotrophic glutamate receptor 1 (mGluR1) and p53 were investigated. In C17.2 cells, irradiation significantly increased the neurite outgrowth, a morphological hallmark of neuronal differentiation, in a dose-dependent manner. Also, the expression levels of neuronal marker proteins, ?-III tubulin were increased by IR. To investigate whether IR-induced differentiation is normal, the expression of neuronal function-related genes including synaptophysin, a synaptic vesicle forming proteins, synaptotagmin1, a calcium ion sensor, ?-aminobutyric acid (GABA) receptors, inhibitory neurotransmitter receptors and glutamate receptors, excitatory neurotransmitter receptors was examined and compared to that of neurotrophin-stimulated differentiation. IR increased the expression of synaptophysin, synaptotagmin1 and GABA receptors mRNA similarly to normal differentiation by stimulation of neurotrophin. Interestingly, the overall expression of glutamate receptors was significantly higher in irradiated group than normal differentiation group, suggesting that the IR-induced neuronal differentiation may cause altered neuronal function in C17.2 cells. Next, the molecular mechanism of the altered neuronal differentiation induced by IR was studied by investigating signaling pathways including p53, mGluR1, STAT3 and PI3K. Increases of neurite outgrowth, neuronal marker and neuronal function-related gene expressions by IR were abolished by inhibition of p53, mGluR-1, STAT3 or PI3K. The inhibition of PI3K blocked both p53 signaling and STAT3-mGluR1 signaling but inhibition of p53 did not affect STAT3-mGluR1 signaling in irradiated C17.2 cells. Finally, these results of the IR-induced altered differentiation in C17.2 cells were verified in ex vivo experiments using mouse primary neural stem cells. In conclusion, the results of this study demonstrated that IR is able to trigger the altered neuronal differentiation in undifferentiated neural stem-like cells through PI3K-STAT3-mGluR1 and PI3K-p53 signaling. It is suggested that the IR-induced altered neuronal differentiation may play a role in the brain dysfunction caused by IR.

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Dataset Information

GDF11 induces differentiation and apoptosis and inhibits migration of C17.2 neural stem cells via modulating MAPK signaling pathway.

Publications

GDF11 induces differentiation and apoptosis and inhibits migration of C17.2 neural stem cells via modulating MAPK signaling pathway.

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