title: Synaptic polarity depends on phosphatidylinositol signaling regulated by myo-inositol monophosphatase in Caenorhabditis elegans.
abstract: Although neurons are highly polarized, how neuronal polarity is generated remains poorly understood. An evolutionarily conserved inositol-producing enzyme myo-inositol monophosphatase (IMPase) is essential for polarized localization of synaptic molecules in Caenorhabditis elegans and can be inhibited by lithium, a drug for bipolar disorder. The synaptic defect of IMPase mutants causes defects in sensory behaviors including thermotaxis. Here we show that the abnormalities of IMPase mutants can be suppressed by mutations in two enzymes, phospholipase Cβ or synaptojanin, which presumably reduce the level of membrane phosphatidylinositol 4,5-bisphosphate (PIP(2)). We also found that mutations in phospholipase Cβ conferred resistance to lithium treatment. Our results suggest that reduction of PIP(2) on plasma membrane is a major cause of abnormal synaptic polarity in IMPase mutants and provide the first in vivo evidence that lithium impairs neuronal PIP(2) synthesis through inhibition of IMPase. We propose that the PIP(2) signaling regulated by IMPase plays a novel and fundamental role in the synaptic polarity.
authors.affiliation: Laboratory of Molecular Neurobiology, Division of Biological Science, Graduate School of Science, Nagoya University, Nagoya 464-8602, Japan.
authors.forename: Tsubasa
authors.initials: T
authors.lastname: Kimata
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Tanizawa
authors.forename: Yoko
authors.initials: Y
authors.lastname: Can
authors.forename: Shingo
authors.initials: S
authors.lastname: Ikeda
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kuhara
authors.forename: Ikue
authors.initials: I
authors.lastname: Mori
mesh_terms: D015720:5'-Nucleotidase / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D018021:Lithium Chloride / Q000494:pharmacology; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism*; D054799:Phospholipase C beta / Q000235:genetics; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D021381:Protein Transport; D015398:Signal Transduction; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*
chemical_list: D029742:Caenorhabditis elegans Proteins; D009419:Nerve Tissue Proteins; D010716:Phosphatidylinositols; C423186:UNC-104 protein, C elegans; D010744:Phosphoric Monoester Hydrolases; C021822:myo-inositol-1 (or 4)-monophosphatase; D015720:5'-Nucleotidase; C517632:Egl-8 protein, C elegans; D054799:Phospholipase C beta; D018021:Lithium Chloride