Zebrafish knockout of Down syndrome gene, DYRK1A, shows social impairments relevant to autism

Cho

et al. 2018

Preprint

Self Cite

DYRK1A is a major causative gene in Down syndrome (DS). Reduced incidence of solid tumors and vascular anomalies in DS patients suggests a role of DYRK1A in angiogenesis, but in vivo evidence is lacking. 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 kinasedead 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 dyrk1aa 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.All rights reserved. No reuse allowed without permission.(which was not peer-reviewed) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.

Section: Cerebral Hemorrhage and A Vascular Phenotype Of Dyrk1aa Krb1mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Vascular defects ofDYRK1Aknockouts are ameliorated by modulating calcium signaling in zebrafish

Cho

et al. 2018

Preprint

Self Cite

“…dyrk1aa homozygous KO zebrafish were used as ASD animal models as these fish have been shown to exhibit social impairment. 3 WT and the dyrk1aa homozygous KO zebrafish line were obtained from the Zebrafish Center for Disease Modeling (ZCDM), Korea (http://knrrb.knrrc.or.kr/english/index.jsp?rrb=zcdm).…”

Section: Zebrafish Maintenancementioning

confidence: 99%

“…1,2 For example, adult zebrafish exhibit a variety of behaviors that can be easily induced and quantified relevant to the analysis and modeling of autism spectrum disorder (ASD). 3 In addition, zebrafish are also utilized in psychopharmacology, for example, for screening neuroactive drugs for efficacy in central nervous system (CNS) disease models. 4 Numerous features of shoal mates, or conspecifics, have been suggested to influence shoaling (social preference)-related responses.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The Body Size of Stimulus Conspecifics Affects Social Preference in a Binary Choice Task in Wild-Type, But Not in dyrk1aa Mutant, Zebrafish

et al. 2019

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The zebrafish has become an appropriate animal model in the analysis of numerous human brain disorders. A variety of neuropsychiatric conditions and neurodevelopmental disorders are comorbid with abnormal social behavior. Given the translational relevance of zebrafish, multidisciplinary studies employing behavioral, neurobiological, and molecular methods with this species may provide insights into human central nervous system (CNS) disorders. Many of these studies impinge upon our ability to properly induce and quantify the behavior of zebrafish, a relatively understudied aspect of this species. In this study, we investigate how the body size of conspecifics relative to that of the test subject influences social (shoaling) responses in zebrafish. We found a robust preference by wild-type (WT) test zebrafish toward big conspecifics, but not toward smaller conspecifics. Additionally, we tested an autism-relevant zebrafish knockout (KO) model. The dyrk1aa KO zebrafish showed impaired social preference compared with WT in the social behavior test. Our results confirm the effect of relative body size on social preference and that the social preference task developed for zebrafish may uncover the function of genes and biological mechanisms potentially associated with human CNS disorders.

Functions ofSRPK,CLKandDYRKkinases in stem cells, development, and human developmental disorders

Hogg,

Findlay

2023

FEBS Letters

Human developmental disorders encompass a wide range of debilitating physical conditions and intellectual disabilities. Perturbation of protein kinase signalling underlies the development of some of these disorders. For example, disrupted SRPK signalling is associated with intellectual disabilities, and the gene dosage of DYRKs can dictate the pathology of disorders including Down's syndrome. Here, we review the emerging roles of the CMGC kinase families SRPK, CLK, DYRK, and sub‐family HIPK during embryonic development and in developmental disorders. In particular, SRPK, CLK, and DYRK kinase families have key roles in developmental signalling and stem cell regulation, and can co‐ordinate neuronal development and function. Genetic studies in model organisms reveal critical phenotypes including embryonic lethality, sterility, musculoskeletal errors, and most notably, altered neurological behaviours arising from defects of the neuroectoderm and altered neuronal signalling. Further unpicking the mechanisms of specific kinases using human stem cell models of neuronal differentiation and function will improve our understanding of human developmental disorders and may provide avenues for therapeutic strategies.