RRC ID 44922
Author Ohnishi T, Murata T, Watanabe A, Hida A, Ohba H, Iwayama Y, Mishima K, Gondo Y, Yoshikawa T.
Title Defective craniofacial development and brain function in a mouse model for depletion of intracellular inositol synthesis.
Journal J. Biol. Chem.
Abstract myo-Inositol is an essential biomolecule that is synthesized by myo-inositol monophosphatase (IMPase) from inositol monophosphate species. The enzymatic activity of IMPase is inhibited by lithium, a drug used for the treatment of mood swings seen in bipolar disorder. Therefore, myo-inositol is thought to have an important role in the mechanism of bipolar disorder, although the details remain elusive. We screened an ethyl nitrosourea mutant mouse library for IMPase gene (Impa) mutations and identified an Impa1 T95K missense mutation. The mutant protein possessed undetectable enzymatic activity. Homozygotes died perinatally, and E18.5 embryos exhibited striking developmental defects, including hypoplasia of the mandible and asymmetric fusion of ribs to the sternum. Perinatal lethality and morphological defects in homozygotes were rescued by dietary myo-inositol. Rescued homozygotes raised on normal drinking water after weaning exhibited a hyper-locomotive trait and prolonged circadian periods, as reported in rodents treated with lithium. Our mice should be advantageous, compared with those generated by the conventional gene knock-out strategy, because they carry minimal genomic damage, e.g. a point mutation. In conclusion, our results reveal critical roles for intracellular myo-inositol synthesis in craniofacial development and the maintenance of proper brain function. Furthermore, this mouse model for cellular inositol depletion could be beneficial for understanding the molecular mechanisms underlying the clinical effect of lithium and myo-inositol-mediated skeletal development.
Volume 289(15)
Pages 10785-96
Published 2014-4-11
DOI 10.1074/jbc.M113.536706
PII M113.536706
PMID 24554717
PMC PMC4036449
MeSH Amino Acid Sequence Animals Behavior, Animal Bipolar Disorder / drug therapy Brain / metabolism* Brain Diseases / drug therapy Circadian Rhythm Disease Models, Animal Ethylnitrosourea / chemistry Female Gene Library Genotype Homozygote Humans Inositol / biosynthesis* Lithium / pharmacology* Male Mice Mice, Inbred C57BL Molecular Sequence Data Mutagenesis Mutation Mutation, Missense Phosphoric Monoester Hydrolases / genetics Phosphoric Monoester Hydrolases / metabolism* Recombinant Proteins / metabolism Sequence Homology, Amino Acid Time Factors
IF 4.011
Times Cited 5
Human and Animal Cells