title: Involvement of platelet-activating factor and LIS1 in neuronal migration.
abstract: Platelet-activating factor (PAF, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is a biologically active lipid mediator. We have previously shown the expression of PAF receptor in neurons and microglia. PAF is produced in the brain from its precursor, and degraded by the enzyme PAF acetylhydrolase. LIS1 is a regulatory subunit of PAF acetylhydrolase, and is identical to a gene whose deletion causes the human neuronal migration disorder, type I lissencephaly. Indeed, Lis1 mutant mice display defects in neuronal migration and layering in vivo, and also in cerebellar granule cell migration in vitro. However, the roles of PAF and the PAF receptor in the neuronal migration remain to be determined. Here, we show that PAF receptor-deficient mice exhibited histological abnormalities in the embryonic cerebellum. PAF receptor-deficient cerebellar granule neurons migrated more slowly in vitro than wild-type neurons, consistent with the observation that a PAF receptor antagonist reduced the migration of wild-type neurons in vitro. Synergistic reduction of neuronal migration was observed in a double mutant of PAF receptor and LIS1. Unexpectedly, PAF affected the migration of PAF receptor-deficient neurons, suggesting a receptor-independent pathway for PAF action. The PAF receptor-independent response to PAF was abolished in granule neurons derived from the double mutant mice. Thus, our results suggest that the migration of cerebellar granule cells is regulated by PAF through receptor-dependent and receptor-independent pathways, and that LIS1 is a pivotal molecule that links PAF action and neuronal cell migration both in vivo and in vitro.
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Medicine, The University of Tokyo, CREST of JST, Tokyo 113-0033, Japan.
authors.forename: Suzumi M
authors.initials: SM
authors.lastname: Tokuoka
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ishii
authors.forename: Noriko
authors.initials: N
authors.lastname: Kawamura
authors.forename: Mamoru
authors.initials: M
authors.lastname: Satoh
authors.forename: Atsuyoshi
authors.initials: A
authors.lastname: Shimada
authors.forename: Shinji
authors.initials: S
authors.lastname: Sasaki
authors.forename: Shinji
authors.initials: S
authors.lastname: Hirotsune
authors.forename: Anthony
authors.initials: A
authors.lastname: Wynshaw-Boris
authors.forename: Takao
authors.initials: T
authors.lastname: Shimizu
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D000818:Animals; D002465:Cell Movement / Q000502:physiology; D002531:Cerebellum / Q000002:abnormalities / Q000166:cytology / Q000196:embryology; D000013:Congenital Abnormalities / Q000503:physiopathology; D004622:Embryo, Mammalian / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D010972:Platelet Activating Factor / Q000502:physiology*; D010980:Platelet Membrane Glycoproteins / Q000502:physiology; D011956:Receptors, Cell Surface / Q000502:physiology; D043562:Receptors, G-Protein-Coupled
chemical_list: D008869:Microtubule-Associated Proteins; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C513190:Pafah1b1 protein, mouse