PUBLICATION

Vascular defects of DYRK1A knockouts are ameliorated by modulating calcium signaling in zebrafish

Authors
Cho, H.J., Lee, J.G., Kim, J.H., Kim, S.Y., Huh, Y.H., Kim, H.J., Lee, K.S., Yu, K., Lee, J.S.
ID
ZDB-PUB-190507-7
Date
2019
Source
Disease models & mechanisms   12(5): (Journal)
Registered Authors
Lee, Jeong-Soo
Keywords
DYRK1A, Hemorrhage, Vascular development, Zebrafish embryo
Datasets
GEO:GSE123026, GEO:GSE111280
MeSH Terms
  • Animals
  • Blood Vessels/drug effects
  • Blood Vessels/pathology*
  • Brain/blood supply
  • Brain/embryology
  • Brain/pathology
  • Brain/ultrastructure
  • Calcium Signaling*
  • Cerebral Hemorrhage/pathology
  • Egtazic Acid/pharmacology
  • Embryo, Nonmammalian/metabolism
  • Embryo, Nonmammalian/pathology
  • Embryonic Development/drug effects
  • Endothelial Cells/drug effects
  • Endothelial Cells/metabolism
  • Gene Knockout Techniques*
  • Harmine/pharmacology
  • Intracellular Space/metabolism
  • Mutation/genetics
  • Phenotype
  • Protein Kinases/metabolism*
  • Transcriptome/genetics
  • Zebrafish/embryology
  • Zebrafish/metabolism*
  • Zebrafish Proteins/antagonists & inhibitors
  • Zebrafish Proteins/metabolism*
PubMed
31043432 Full text @ Dis. Model. Mech.
Abstract
DYRK1A is a major causative gene in Down syndrome (DS). Reduced incidence of solid tumors such as neuroblastoma in DS patients and increased vascular anomalies in DS fetuses suggest a potential role of DYRK1A in angiogenic processes, but in vivo evidence is still scarce. Here, we used zebrafish dyrk1aa mutant embryos to understand DYRK1A function in the cerebral vasculature formation. Zebrafish dyrk1aa mutants exhibited cerebral hemorrhage and defects in angiogenesis of central arteries in the developing hindbrain. Such phenotypes were rescued by wild-type dyrk1aa mRNA, but not by a kinase-dead form, indicating the importance of DYRK1A kinase activity. Chemical screening using a bioactive small molecule library identified a calcium chelator, EGTA, as one of the hits that most robustly rescued the hemorrhage. Vascular defects of mutants were also rescued by independent modulation of calcium signaling by FK506. Furthermore, the transcriptomic analyses supported the alterations of calcium signaling networks in dyrk1aa mutants. Together, our results suggest that DYRK1A plays an essential role in angiogenesis and in maintenance of the developing cerebral vasculature via regulation of calcium signaling, which may have therapeutic potential for DYRK1A-related vascular diseases.
Genes / Markers
Figures
Show all Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping