Format

Send to

Choose Destination
Dis Model Mech. 2019 May 23;12(5). pii: dmm037044. doi: 10.1242/dmm.037044.

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

Cho HJ1,2,3, Lee JG1,2, Kim JH2,4, Kim SY2,4, Huh YH5, Kim HJ5, Lee KS2,6, Yu K1,2,3, Lee JS7,3.

Author information

1
Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea.
2
KRIBB School, University of Science and Technology, 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea.
3
Dementia DTC R&D Convergence Program, Korea Institute of Science and Technology, Hwarang-ro 14-gil 5, Seongbuk-gu, Seoul, 02792, Republic of Korea.
4
Genome Editing Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea.
5
Electron Microscopy Research Center, Korea Basic Science Institute, 162 Yeongudanji-ro, Ochang-eup, Cheongwon-gu, Cheongju-si, Chungcheongbuk-do, 28119, Republic of Korea.
6
Hazards Monitoring BNT Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea.
7
Disease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon, 34141, Republic of Korea jeongsoo@kribb.re.kr.

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 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.

KEYWORDS:

DYRK1A; Hemorrhage; Vascular development; Zebrafish embryo

Conflict of interest statement

Competing interestsThe authors declare no competing or financial interests.

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center