title: Chronic glucocorticoid exposure suppressed the differentiation and survival of embryonic neural stem/progenitor cells: Possible involvement of ERK and PI3K/Akt signaling in the neuronal differentiation.
abstract: Growing evidence suggests that excess glucocorticoids (GCs) exposure during the pregnancy results in behavioral abnormality in offspring. Although research using animal models has demonstrated that systemic GCs treatment impairs development of fetal brain, direct impact of GCs on the phenotype of embryonic neural stem/progenitor cells (eNSPCs) and its mechanism has not been fully understood. Here, we investigated the effect of chronic GCs exposure on cell proliferation, differentiation, and survival of eNSPCs in vitro. Corticosterone (CORT, a murine GC) treatment did not affect the proliferation of eNSPCs. On the other hand, decreased expression of neuronal, synaptic, and astroglial marker proteins were observed when the differentiation of eNSPCs was induced in the presence of CORT. CORT also reduced the survival rate of eNSPCs after the differentiation. Moreover, CORT inhibited extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase/Akt (PI3K/Akt) signaling pathways, which were activated during cell differentiation of eNSPCs. Inhibiting these signaling pathways reduced neural differentiation and eNSPCs viability, indicating their essential roles in the eNSPCs differentiation. Furthermore, IGF-I, a potent PI3K/Akt and ERK signaling stimulator, partially restored the adverse effect of CORT on eNSPCs, suggesting a possible involvement of the repression of these intracellular signaling in the GCs-caused eNSPCs impairment.
authors.affiliation: Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan; Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University, Tokyo, Japan.
authors.forename: Haruki
authors.initials: H
authors.lastname: Odaka
authors.affiliation: Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan; Department of Cell Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan. Electronic address: numakawa.yyrmk@gmail.com.
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Numakawa
authors.affiliation: Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Yoshimura
authors.affiliation: Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan; Faculty of Health Science, Hokkaido University, Sapporo, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Nakajima
authors.affiliation: Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan; Department of Biomedical Chemistry, School of Science and Technology, Kwansei Gakuin University, Sanda, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Adachi
authors.affiliation: Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan; Department of Molecular Pharmacology, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Ooshima
authors.affiliation: Department of Life Science and Medical Bioscience, School of Advanced Science and Engineering, Waseda University, Tokyo, Japan.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Department of Mental Disorder Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kunugi
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003345:Corticosterone / Q000009:adverse effects*; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005938:Glucocorticoids / Q000009:adverse effects*; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects*; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017208:Rats, Wistar; D015398:Signal Transduction
chemical_list: D005938:Glucocorticoids; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D003345:Corticosterone
keywords: Cell survival; Corticosterone; Differentiation; Extracellular signal-regulated kinase; Glucocorticoid; Neural stem cell; Phosphatidylinositol 3-kinase