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

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 in angiogenic processes, but evidence is still scarce. Here, we used zebrafish mutant embryos to understa...

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Bibliographic Details
Published in:Disease models & mechanisms 2019-05, Vol.12 (5)
Main Authors: Cho, Hyun-Ju, Lee, Jae-Geun, Kim, Jong-Hwan, Kim, Seon-Young, Huh, Yang Hoon, Kim, Hyo-Jeong, Lee, Kyu-Sun, Yu, Kweon, Lee, Jeong-Soo
Format: Article
Language:English
Subjects:
Angiogenesis
Animals
Blood Vessels - drug effects
Blood Vessels - pathology
Brain - blood supply
Brain - embryology
Brain - pathology
Brain - ultrastructure
Calcium Signaling
Cerebral Hemorrhage - pathology
Down syndrome
DYRK1A
Egtazic Acid - pharmacology
Embryo, Nonmammalian - metabolism
Embryo, Nonmammalian - pathology
Embryonic Development - drug effects
Endothelial Cells - drug effects
Endothelial Cells - metabolism
Gene Knockout Techniques
Genotype & phenotype
Harmine - pharmacology
Hemorrhage
Intracellular Space - metabolism
Kinases
Microscopy
Mutation - genetics
Pathogenesis
Permeability
Phenotype
Protein Kinases - metabolism
Transcriptome - genetics
Vascular development
Zebra
Zebrafish - embryology
Zebrafish - metabolism
Zebrafish embryo
Zebrafish Proteins - antagonists & inhibitors
Zebrafish Proteins - metabolism
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Summary: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 in angiogenic processes, but evidence is still scarce. Here, we used zebrafish mutant embryos to understand function in cerebral vasculature formation. Zebrafish mutants exhibited cerebral hemorrhage and defects in angiogenesis of central arteries in the developing hindbrain. Such phenotypes were rescued by wild-type 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 mutants. Together, our results suggest that 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 -related vascular diseases.
ISSN:1754-8403
1754-8411
DOI:10.1242/dmm.037044