title: Ionizing Radiation Induces Altered Neuronal Differentiation by mGluR1 through PI3K-STAT3 Signaling in C17.2 Mouse Neural Stem-Like Cells.
abstract: 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, β-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, γ-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.
authors.affiliation: Radiation Biotechnology Research Division, Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup, Republic of Korea.|Department of Biochemistry, College of Natural Sciences, Chungnam National University, Daejeon, Republic of Korea.
authors.forename: Hyeon Soo
authors.initials: HS
authors.lastname: Eom
authors.affiliation: Radiation Biotechnology Research Division, Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup, Republic of Korea.|Department of Radiation Biotechnology and Applied Radioisotope, University of Science and Technology (UST), Daejeon, Republic of Korea.
authors.forename: Hae Ran
authors.initials: HR
authors.lastname: Park
authors.affiliation: Radiation Biotechnology Research Division, Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup, Republic of Korea.|Department of Radiation Biotechnology and Applied Radioisotope, University of Science and Technology (UST), Daejeon, Republic of Korea.
authors.forename: Sung Kee
authors.initials: SK
authors.lastname: Jo
authors.affiliation: Department of Biochemistry, College of Natural Sciences, Chungnam National University, Daejeon, Republic of Korea.
authors.forename: Young Sang
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Department of Veterinary Anatomy, College of Veterinary Medicine, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Changjong
authors.initials: C
authors.lastname: Moon
authors.affiliation: Department of Veterinary Anatomy, College of Veterinary Medicine, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Sung-Ho
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Radiation Biotechnology Research Division, Advanced Radiation Technology Institute, Korea Atomic Energy Research Institute, Jeongeup, Republic of Korea.|Department of Radiation Biotechnology and Applied Radioisotope, University of Science and Technology (UST), Daejeon, Republic of Korea.
authors.forename: Uhee
authors.initials: U
authors.lastname: Jung
mesh_terms: D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000528:radiation effects*; D002460:Cell Line; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D005998:Glycine / Q000031:analogs & derivatives / Q000494:pharmacology; D007150:Immunohistochemistry; D008810:Mice, Inbred C57BL; D009414:Nerve Growth Factors / Q000494:pharmacology; D058953:Neural Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011839:Radiation, Ionizing; D060888:Real-Time Polymerase Chain Reaction; D018079:Receptors, GABA / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000528:radiation effects*; D016708:Synaptophysin / Q000378:metabolism; D050857:Synaptotagmins / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D001565:Benzoates; D015415:Biomarkers; D009414:Nerve Growth Factors; D018079:Receptors, GABA; D018094:Receptors, Metabotropic Glutamate; D050796:STAT3 Transcription Factor; D016708:Synaptophysin; D016159:Tumor Suppressor Protein p53; C104077:metabotropic glutamate receptor type 1; D050857:Synaptotagmins; C079694:alpha-methyl-4-carboxyphenylglycine; D019869:Phosphatidylinositol 3-Kinases; D005998:Glycine
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