Impaired dendritic growth and positioning of cortical pyramidal neurons by activation of aryl hydrocarbon receptor signaling in the developing mouse

• Published in: PloS one Vol. 12; no. 8; p. e0183497
• Main Authors: Kimura, Eiki, Kubo, Ken-Ichiro, Endo, Toshihiro, Ling, Wenting, Nakajima, Kazunori, Kakeyama, Masaki, Tohyama, Chiharu
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 18.08.2017; Public Library of Science (PLoS)
• Subjects: Abnormalities; Activation analysis; Animals; Aromatic compounds; Biology; Biology and Life Sciences; Brain; Brain research; Cell migration; Cerebral cortex; Cerebrum; Cortex (somatosensory); Dendrites; Dendritic branching; Dendritic cells; Dendritic structure; Dioxins; Electroporation; Embryos; Environmental health; Genetic aspects; Health sciences; Helix-loop-helix proteins; Helix-loop-helix proteins (basic); Hydrocarbons; Insulin-like growth factors; Integrative medicine; Invertebrates; Laboratories; Laboratory animals; Laboratory tests; Ligands; Mammals; Medicine and Health Sciences; Mice; Mice, Inbred C57BL; Morphology; Nervous system; Neurons; Perinatal exposure; Physiological aspects; Pollutants; Preventive medicine; Pyramidal cells; Pyramidal Cells - metabolism; Receptors, Aryl Hydrocarbon - metabolism; Research and Analysis Methods; Rodents; Signal Transduction; Somatosensory cortex; Stems; Transcription activation; Transcription factors; Vertebrates; Japan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0183497

The basic helix-loop-helix (bHLH) transcription factors exert multiple functions in mammalian cerebral cortex development. The aryl hydrocarbon receptor (AhR), a member of the bHLH-Per-Arnt-Sim subfamily, is a ligand-activated transcription factor reported to regulate nervous system development in both invertebrates and vertebrates, but the functions that AhR signaling pathway may have for mammalian cerebral cortex development remains elusive. Although the endogenous ligand involved in brain developmental process has not been identified, the environmental pollutant dioxin potently binds AhR and induces abnormalities in higher brain function of laboratory animals. Thus, we studied how activation of AhR signaling influences cortical development in mice. To this end, we produced mice expressing either constitutively active-AhR (CA-AhR), which has the capacity for ligand-independent activation of downstream genes, or AhR, which requires its ligands for activation. In brief, CA-AhR-expressing plasmid and AhR-expressing plasmid were each transfected into neural stems cells in the developing cerebrum by in utero electroporation on embryonic day 14.5. On postnatal day 14, mice transfected in utero with CA-AhR, but not those transfected with AhR, exhibited drastically reduced dendritic arborization of layer II/III pyramidal neurons and impaired neuronal positioning in the developing somatosensory cortex. The effects of CA-AhR were observed for dendrite development but not for the commissural fiber projection, suggesting a preferential influence on dendrites. The present results indicate that over-activation of AhR perturbs neuronal migration and morphological development in mammalian cortex, supporting previous observations of impaired dendritic structure, cortical dysgenesis, and behavioral abnormalities following perinatal dioxin exposure.