title: Stereotyped fetal brain disorganization is induced by hypoxia and requires lysophosphatidic acid receptor 1 (LPA1) signaling.
abstract: Fetal hypoxia is a common risk factor that has been associated with a range of CNS disorders including epilepsy, schizophrenia, and autism. Cellular and molecular mechanisms through which hypoxia may damage the developing brain are incompletely understood but are likely to involve disruption of the laminar organization of the cerebral cortex. Lysophosphatidic acid (LPA) is a bioactive lipid capable of cortical influences via one or more of six cognate G protein-coupled receptors, LPA(1-6), several of which are enriched in fetal neural progenitor cells (NPCs). Here we report that fetal hypoxia induces cortical disruption via increased LPA(1) signaling involving stereotyped effects on NPCs: N-cadherin disruption, displacement of mitotic NPCs, and impaired neuronal migration, as assessed both ex vivo and in vivo. Importantly, genetic removal or pharmacological inhibition of LPA(1) prevented the occurrence of these hypoxia-induced phenomena. Hypoxia resulted in overactivation of LPA(1) through selective inhibition of G protein-coupled receptor kinase 2 expression and activation of downstream pathways including G(αi) and Ras-related C3 botulinum toxin substrate 1. These data identify stereotyped and selective hypoxia-induced cerebral cortical disruption requiring LPA(1) signaling, inhibition of which can reduce or prevent disease-associated sequelae, and may take us closer to therapeutic treatment of fetal hypoxia-induced CNS disorders and possibly other forms of hypoxic injury.
authors: Department of Molecular Biology, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors: Keira Joann
authors: KJ
authors: Herr
authors: Deron R
authors: DR
authors: Herr
authors: Chang-Wook
authors: CW
authors: Lee
authors: Kyoko
authors: K
authors: Noguchi
authors: Jerold
authors: J
authors: Chun
mesh_terms: D000818:Animals; D001921:Brain / Q000196:embryology* / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement; D002540:Cerebral Cortex / Q000196:embryology / Q000201:enzymology / Q000473:pathology; D005260:Female; D005333:Fetus / Q000378:metabolism / Q000473:pathology*; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008938:Mitosis; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D049368:Receptors, Lysophosphatidic Acid; C496568:GRK2 protein, mouse; D054769:G-Protein-Coupled Receptor Kinase 2