Abstract
ABSTRACTDYRK1A 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 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.
Highlights
The cerebral vasculature plays an essential role in maintaining the homeostasis of the brain by providing oxygen and nutrients and removing waste products
Cerebral hemorrhage and a vascular phenotype of dyrk1aakrb1 mutant embryos We recently reported the generation of the dyrk1aakrb1 mutants that displayed microcephaly and autistic behavioral phenotypes in adults, whereas no distinct morphological defects were observed during embryogenesis (Kim et al, 2017)
We established a less-known function of Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A), one of the critical genes contributing to some Down syndrome (DS) phenotypes, in regulating angiogenesis and preventing hemorrhage in the brain, using zebrafish dyrk1aa knockout mutants
Summary
The cerebral vasculature plays an essential role in maintaining the homeostasis of the brain by providing oxygen and nutrients and removing waste products. New branches of the cerebral vasculature are formed through angiogenesis by endothelial cells, the primary cell component of the vasculature, via complex cell-cell interactions and signaling pathways from existing vessels. The cerebral vasculature contributes to the formation of the neurovascular unit (NVU), which comprises pericytes, astrocytes, microglia and neurons in addition to endothelial cells. The inappropriate development of cerebral endothelial cells may lead to defects in angiogenesis and/or endothelial permeability, which are closely linked to vascular pathologies such as vascular malformations and stroke (Folkman, 1995; Pandya et al, 2006)
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