title: Ketamine exposure in early development impairs specification of the primary germ cell layers.
abstract: Preclinical and clinical evidence implicates N-methyl-d-aspartate receptor (NMDAr) signaling in early embryological development. However, the role of NMDAr signaling in early development has not been well studied. Here, we use a mouse embryonic stem cell model to perform a step-wise exploration of the effects of NMDAr signaling on early cell fate specification. We found that antagonism of the NMDAr impaired specification into the neuroectodermal and mesoendodermal cell lineages, with little or no effect on specification of the extraembryonic endoderm cell lineage. Consistent with these findings, exogenous NMDA promoted neuroectodermal differentiation. Finally, NMDAr antagonism modified expression of several key targets of TGF-β superfamily signaling, suggesting a mechanism for these findings. In summary, this study shows that NMDAr antagonism interferes with the normal developmental pathways of embryogenesis, and suggests that interference is most pronounced prior to neuroectodermal and mesoendodermal cell fate specification.
authors.affiliation: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; The Howard Hughes Medical Institute, Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA. Electronic address: oluwaseun.akeju@mgh.harvard.edu.
authors.forename: Oluwaseun
authors.initials: O
authors.lastname: Akeju
authors.affiliation: The Howard Hughes Medical Institute, Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Brandi N
authors.initials: BN
authors.lastname: Davis-Dusenbery
authors.affiliation: The Howard Hughes Medical Institute, Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Seth H
authors.initials: SH
authors.lastname: Cassel
authors.affiliation: The Howard Hughes Medical Institute, Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Justin K
authors.initials: JK
authors.lastname: Ichida
authors.affiliation: The Howard Hughes Medical Institute, Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Eggan
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002658:Developmental Disabilities / Q000209:etiology*; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D058732:Embryoid Bodies / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D047108:Embryonic Development / Q000187:drug effects*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D005434:Flow Cytometry; D007649:Ketamine / Q000494:pharmacology*; D008297:Male; D051379:Mice; D046228:Microarray Analysis; D009046:Motor Neurons / Q000187:drug effects; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000139:chemically induced* / Q000503:physiopathology*
chemical_list: D018691:Excitatory Amino Acid Antagonists; D009419:Nerve Tissue Proteins; D007649:Ketamine; D016291:Dizocilpine Maleate
keywords: Differentiation; Ketamine; Mesoendoderm; Mouse embryonic stem cells; NMDA; Neurogenesis
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