title: Down-regulation of coasy, the gene associated with NBIA-VI, reduces Bmp signaling, perturbs dorso-ventral patterning and alters neuronal development in zebrafish.
abstract: Mutations in Pantothenate kinase 2 and Coenzyme A (CoA) synthase (COASY), genes involved in CoA biosynthesis, are associated with rare neurodegenerative disorders with brain iron accumulation. We showed that zebrafish pank2 gene plays an essential role in brain and vasculature development. Now we extended our study to coasy. The gene has high level of sequence identity with the human ortholog and is ubiquitously expressed from the earliest stages of development. The abrogation of its expression led to strong reduction of CoA content, high lethality and a phenotype resembling to that of dorsalized mutants. Lower doses of morpholino resulted in a milder phenotype, with evident perturbation in neurogenesis and formation of vascular arborization; the dorso-ventral patterning was severely affected, the expression of bone morphogenetic protein (Bmp) receptors and activity were decreased, while cell death increased. These features specifically correlated with the block in CoA biosynthesis and were rescued by the addition of CoA to fish water and the overexpression of the human wild-type, but not mutant gene. These results confirm the absolute requirement for adequate levels of CoA for proper neural and vascular development in zebrafish and point to the Bmp pathway as a possible molecular connection underlining the observed phenotype.
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, viale Europa 11, 25123 Brescia, Italy.
authors.forename: Deepak
authors.initials: D
authors.lastname: Khatri
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, viale Europa 11, 25123 Brescia, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Zizioli
authors.affiliation: Department of Biology, University of Padova, via U. Bassi 58/B, 35131, Padova, Italy.
authors.forename: Natascia
authors.initials: N
authors.lastname: Tiso
authors.affiliation: Department of Biology, University of Padova, via U. Bassi 58/B, 35131, Padova, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Facchinello
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, viale Europa 11, 25123 Brescia, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Vezzoli
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, viale Europa 11, 25123 Brescia, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Gianoncelli
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, viale Europa 11, 25123 Brescia, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Memo
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, viale Europa 11, 25123 Brescia, Italy.
authors.forename: Eugenio
authors.initials: E
authors.lastname: Monti
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, viale Europa 11, 25123 Brescia, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Borsani
authors.affiliation: Department of Molecular and Translational Medicine, University of Brescia, viale Europa 11, 25123 Brescia, Italy.|Clinical Chemistry Laboratory, ASST Spedali Civili di Brescia, 25123 Brescia, Italy.
authors.forename: Dario
authors.initials: D
authors.lastname: Finazzi
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D019521:Body Patterning / Q000187:drug effects / Q000235:genetics; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D001921:Brain / Q000196:embryology / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D003065:Coenzyme A / Q000378:metabolism; D003198:Computer Simulation; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics*; D004625:Embryo, Nonmammalian / Q000187:drug effects / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006801:Humans; D008845:Microinjections; D060172:Morpholinos / Q000494:pharmacology; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000235:genetics; D009474:Neurons / Q000378:metabolism*; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013997:Time Factors; D014166:Transferases / Q000235:genetics* / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics*; D029961:Zebrafish Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D015415:Biomarkers; D019485:Bone Morphogenetic Proteins; D060172:Morpholinos; D012333:RNA, Messenger; D029961:Zebrafish Proteins; D014166:Transferases; C509687:COASY protein, human; C000627692:Coasy protein, zebrafish; D003065:Coenzyme A