Down-regulation of coasy, the gene associated with NBIA-VI, reduces Bmp signaling, perturbs dorso-ventral patterning and alters neuronal development in zebrafish

Khatri, D., Zizioli, D., Tiso, N., Facchinello, N., Vezzoli, S., Gianoncelli, A., Memo, M., Monti, E., Borsani, G., Finazzi, D.
Scientific Reports   6: 37660 (Journal)
Registered Authors
Borsani, Giuseppe, Facchinello, Nicola, Tiso, Natascia
Disease model, Neurodegeneration
MeSH Terms
  • Animals
  • Biomarkers/metabolism
  • Body Patterning*/drug effects
  • Body Patterning*/genetics
  • Bone Morphogenetic Proteins/metabolism*
  • Brain/embryology
  • Brain/metabolism
  • Cell Death/drug effects
  • Coenzyme A/metabolism
  • Computer Simulation
  • Down-Regulation/drug effects
  • Down-Regulation/genetics*
  • Embryo, Nonmammalian/drug effects
  • Embryo, Nonmammalian/metabolism
  • Gene Expression Regulation, Developmental/drug effects
  • Gene Knockdown Techniques
  • Humans
  • Microinjections
  • Morpholinos/pharmacology
  • Neovascularization, Physiologic/drug effects
  • Neovascularization, Physiologic/genetics
  • Neurons/metabolism*
  • Phenotype
  • RNA, Messenger/genetics
  • RNA, Messenger/metabolism
  • Signal Transduction*/drug effects
  • Signal Transduction*/genetics
  • Time Factors
  • Transferases/genetics
  • Transferases/metabolism
  • Zebrafish/embryology*
  • Zebrafish/genetics*
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/metabolism
27892483 Full text @ Sci. Rep.
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.
Genes / Markers
Show all Figures
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes