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 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.

中文翻译：

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DYRK1A基因敲除的血管缺陷可通过调节斑马鱼中的钙信号来改善。

DYRK1A是唐氏综合症（DS）的主要致病基因。DS患者中实体瘤（例如神经母细胞瘤）的发生率降低，DS胎儿中的血管异常增加，提示DYRK1A在血管生成过程中具有潜在作用，但体内证据仍然很少。在这里，我们使用斑马鱼dyrk1aa突变体胚胎来了解DYRK1A在脑血管形成中的功能。斑马鱼dyrk1aa突变体表现出脑出血和发展中的后脑中央动脉血管生成的缺陷。通过野生型dyrk1aa拯救了此类表型mRNA，但不是通过激酶死亡形式，表明DYRK1A激酶活性的重要性。使用具有生物活性的小分子文库进行的化学筛选将钙螯合剂EGTA鉴定为最能有效挽救出血的命中药物之一。还可以通过FK506对钙信号的独立调节来挽救突变体的血管缺陷。此外，转录组学分析支持dyrk1aa突变体中钙信号网络的变化。在一起，我们的结果表明，DYRK1A在血管生成和通过调节钙信号传导在维持发展中的脑血管中起着至关重要的作用，这可能与DYRK1A相关的血管疾病具有治疗潜力。