title: Functional and comparative genomics analyses of pmp22 in medaka fish.
abstract: BACKGROUND
  Pmp22, a member of the junction protein family Claudin/EMP/PMP22, plays an important role in myelin formation. Increase of pmp22 transcription causes peripheral neuropathy, Charcot-Marie-Tooth disease type1A (CMT1A). The pathophysiological phenotype of CMT1A is aberrant axonal myelination which induces a reduction in nerve conduction velocity (NCV). Several CMT1A model rodents have been established by overexpressing pmp22. Thus, it is thought that pmp22 expression must be tightly regulated for correct myelin formation in mammals. Interestingly, the myelin sheath is also present in other jawed vertebrates. The purpose of this study is to analyze the evolutionary conservation of the association between pmp22 transcription level and vertebrate myelin formation, and to find the conserved non-coding sequences for pmp22 regulation by comparative genomics analyses between jawed fishes and mammals.
  
  
  RESULTS
  A transgenic pmp22 over-expression medaka fish line was established. The transgenic fish had approximately one fifth the peripheral NCV values of controls, and aberrant myelination of transgenic fish in the peripheral nerve system (PNS) was observed. We successfully confirmed that medaka fish pmp22 has the same exon-intron structure as mammals, and identified some known conserved regulatory motifs. Furthermore, we found novel conserved sequences in the first intron and 3'UTR.
  
  
  CONCLUSIONS
  Medaka fish undergo abnormalities in the PNS when pmp22 transcription increases. This result indicates that an adequate pmp22 transcription level is necessary for correct myelination of jawed vertebrates. Comparison of pmp22 orthologs between distantly related species identifies evolutionary conserved sequences that contribute to precise regulation of pmp22 expression.
authors.affiliation: Department of Radiation Biomedical Science IV, Radiation Biology Center, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan. jito@m06.mbox.media.kyoto-u.ac.jp
authors.forename: Junji
authors.initials: J
authors.lastname: Itou
authors.forename: Mikita
authors.initials: M
authors.lastname: Suyama
authors.forename: Yukio
authors.initials: Y
authors.lastname: Imamura
authors.forename: Tomonori
authors.initials: T
authors.lastname: Deguchi
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Fujimori
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Yuba
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kawarabayasi
authors.forename: Takashi
authors.initials: T
authors.lastname: Kawasaki
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D001522:Behavior, Animal; D017124:Conserved Sequence / Q000235:genetics; D004558:Electric Stimulation / Q000379:methods; D019143:Evolution, Molecular; D015870:Gene Expression / Q000502:physiology; D023281:Genomics / Q000379:methods*; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D051379:Mice; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009185:Myelin Proteins / Q000502:physiology*; D009431:Neural Conduction / Q000235:genetics; D009990:Oryzias / Q000235:genetics* / Q000254:growth & development / Q000378:metabolism*; D010525:Peripheral Nerves / Q000502:physiology / Q000648:ultrastructure; D011401:Promoter Regions, Genetic / Q000502:physiology; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013550:Swimming / Q000502:physiology; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D009185:Myelin Proteins; D026941:Sodium Channel Blockers; D049452:Green Fluorescent Proteins; D013779:Tetrodotoxin