title: Fluoxetine promotes gliogenesis during neural differentiation in mouse embryonic stem cells.
abstract: Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for treatment of mood disorders and depression, even during pregnancy and lactation. SSRIs are thought to be much safer than tricyclic antidepressants, with a low risk of embryonic toxicity. Several recent studies, however, have reported that fetal exposure to SSRIs increases the risk of adverse effects during fetal and neonatal development. This is consistent with our previous finding that fluoxetine, a prototypical SSRI, profoundly affected the viability of cultured embryonic stem (ES) cells as well as their ability to differentiate into cardiomyocytes. Furthermore, we found that fluoxetine induced fluctuations in ectodermal marker gene expression during ES cell differentiation, which suggests that fluoxetine may affect neural development. In the present study, we investigated the effects of fluoxetine on the process of differentiation from ES cells into neural cells using the stromal cell-derived inducing activity (SDIA) method. Fluoxetine treatment was found to enhance the expression of glial marker genes following neural differentiation, as observed by immunocytochemical analysis or quantitative RT-PCR. The promoter activity of glial marker genes was also significantly enhanced when cells were treated with fluoxetine, as observed by luciferase reporter assay. The expression of neuronal markers during ES cell differentiation into neural cells, on the other hand, was inhibited by fluoxetine treatment. In addition, FACS analysis revealed an increased population of glial cells in the differentiating ES cells treated with fluoxetine. These results suggest that fluoxetine could facilitate the differentiation of mouse ES cells into glial cell lineage, which may affect fetal neural development.
authors.affiliation: Department of Pharmacology, National Research Institute for Child Health and Development, Setagaya, Tokyo, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Kusakawa
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Nakamura
authors.forename: Yuki
authors.initials: Y
authors.lastname: Miyamoto
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sanbe
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Torii
authors.forename: Junji
authors.initials: J
authors.lastname: Yamauchi
authors.forename: Akito
authors.initials: A
authors.lastname: Tanoue
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects*; D019070:Cell Lineage; D018920:Coculture Techniques; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005473:Fluoxetine / Q000494:pharmacology*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D055495:Neurogenesis / Q000187:drug effects*; D009457:Neuroglia / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*
chemical_list: D005473:Fluoxetine; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D017367:Selective Serotonin Reuptake Inhibitors