title: Abnormal cerebellar development and ataxia in CARP VIII morphant zebrafish.
abstract: Congenital ataxia and mental retardation are mainly caused by variations in the genes that affect brain development. Recent reports have shown that mutations in the CA8 gene are associated with mental retardation and ataxia in humans and ataxia in mice. The gene product, carbonic anhydrase-related protein VIII (CARP VIII), is predominantly present in cerebellar Purkinje cells, where it interacts with the inositol 1,4,5-trisphosphate receptor type 1, a calcium channel. In this study, we investigated the effects of the loss of function of CARP VIII during embryonic development in zebrafish using antisense morpholino oligonucleotides against the CA8 gene. Knockdown of CA8 in zebrafish larvae resulted in a curved body axis, pericardial edema and abnormal movement patterns. Histologic examination revealed gross morphologic defects in the cerebellar region and in the muscle. Electron microscopy studies showed increased neuronal cell death in developing larvae injected with CA8 antisense morpholinos. These data suggest a pivotal role for CARP VIII during embryonic development. Furthermore, suppression of CA8 expression leads to defects in motor and coordination functions, mimicking the ataxic human phenotype. This work reveals an evolutionarily conserved function of CARP VIII in brain development and introduces a novel zebrafish model in which to investigate the mechanisms of CARP VIII-related ataxia and mental retardation in humans.
authors.affiliation: Institute of Biomedical Technology and School of Medicine, University of Tampere and BioMediTech, Tampere 33014, Finland. ashok.aspatwar@uta.fi
authors.forename: Ashok
authors.initials: A
authors.lastname: Aspatwar
authors.forename: Martti E E
authors.initials: ME
authors.lastname: Tolvanen
authors.forename: Eija
authors.initials: E
authors.lastname: Jokitalo
authors.forename: Mataleena
authors.initials: M
authors.lastname: Parikka
authors.forename: Csaba
authors.initials: C
authors.lastname: Ortutay
authors.forename: Sanna-Kaisa E
authors.initials: SK
authors.lastname: Harjula
authors.forename: Mika
authors.initials: M
authors.lastname: Rämet
authors.forename: Mauno
authors.initials: M
authors.lastname: Vihinen
authors.forename: Seppo
authors.initials: S
authors.lastname: Parkkila
mesh_terms: D000818:Animals; D001259:Ataxia / Q000235:genetics* / Q000503:physiopathology; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002256:Carbonic Anhydrases / Q000235:genetics* / Q000378:metabolism; D016923:Cell Death / Q000235:genetics; D002531:Cerebellum / Q000002:abnormalities*; D003001:Cloning, Molecular; D019295:Computational Biology; D047108:Embryonic Development; D005260:Female; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D006801:Humans; D020287:In Situ Nick-End Labeling; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics / Q000378:metabolism; D008607:Intellectual Disability / Q000235:genetics / Q000503:physiopathology; D007814:Larva / Q000235:genetics / Q000254:growth & development; D008297:Male; D051379:Mice; D008854:Microscopy, Electron; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000378:metabolism; D010641:Phenotype; D011689:Purkinje Cells / Q000201:enzymology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D015027:Zebrafish / Q000196:embryology*
chemical_list: D014408:Biomarkers, Tumor; D053496:Inositol 1,4,5-Trisphosphate Receptors; D009419:Nerve Tissue Proteins; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D002256:Carbonic Anhydrases