Comparative analysis of genes regulated by Dzip1/<i>iguana</i> and hedgehog in zebrafish

Arnold, Corey; Lamont, Ryan E.; Walker, John T.; Spice, Peter J.; Chan, Chi-Kin; Ho, Chi-Yip; Childs, Sarah J.

doi:10.1002/dvdy.24237

Cited by 19 publications

(19 citation statements)

References 62 publications

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“…Expression of the putative causal gene in the brain of zebrafish larvae was assessed by in-situ hybridisation and compared with that of established pericyte markers notch3 and pdgfrβ . 15 Function of forkhead transcription factor 2 (Foxf2) was assessed by knockout with transcription activator-like effector nucleases (TALENs) to create targeted nonsense mutations in the DNA-binding domain (appendix p 35). Smooth muscle cell coverage of branches of brain vessels was examined in live transgenic mutant and wild-type zebrafish embryos; these smooth muscle cells in zebrafish were modified to express green fluorescent protein with the α-smooth muscle actin promoter (acta2:GFP) at 4–6 days postfertilisation.…”

Section: Methodsmentioning

confidence: 99%

Identification of additional risk loci for stroke and small vessel disease: a meta-analysis of genome-wide association studies

Chauhan¹,

Arnold²,

Chu³

et al. 2016

The Lancet Neurology

135

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Summary Background Genetic determinants of stroke, the leading neurological cause of death and disability, are poorly understood and have seldom been explored in the general population. Our aim was to identify additional loci for stroke by doing a meta-analysis of genome-wide association studies. Methods For the discovery sample, we did a genome-wide analysis of common genetic variants associated with incident stroke risk in 18 population-based cohorts comprising 84 961 participants, of whom 4348 had stroke. Stroke diagnosis was ascertained and validated by the study investigators. Mean age at stroke ranged from 45·8 years to 76·4 years, and data collection in the studies took place between 1948 and 2013. We did validation analyses for variants yielding a significant association (at p<5 × 10−6) with all-stroke, ischaemic stroke, cardioembolic ischaemic stroke, or non-cardioembolic ischaemic stroke in the largest available cross-sectional studies (70 804 participants, of whom 19 816 had stroke). Summary-level results of discovery and follow-up stages were combined using inverse-variance weighted fixed-effects meta-analysis, and in-silico lookups were done in stroke subtypes. For genome-wide significant findings (at p<5 × 10−8), we explored associations with additional cerebrovascular phenotypes and did functional experiments using conditional (inducible) deletion of the probable causal gene in mice. We also studied the expression of orthologs of this probable causal gene and its effects on cerebral vasculature in zebrafish mutants. Findings We replicated seven of eight known loci associated with risk for ischaemic stroke, and identified a novel locus at chromosome 6p25 (rs12204590, near FOXF2) associated with risk of all-stroke (odds ratio [OR] 1·08, 95% CI 1·05–1·12, p=1·48 × 10−8; minor allele frequency 21%). The rs12204590 stroke risk allele was also associated with increased MRI-defined burden of white matter hyperintensity—a marker of cerebral small vessel disease—in stroke-free adults (n=21 079; p=0·0025). Consistently, young patients (aged 2–32 years) with segmental deletions of FOXF2 showed an extensive burden of white matter hyperintensity. Deletion of Foxf2 in adult mice resulted in cerebral infarction, reactive gliosis, and microhaemorrhage. The orthologs of FOXF2 in zebrafish (foxf2b and foxf2a) are expressed in brain pericytes and mutant foxf2b−/− cerebral vessels show decreased smooth muscle cell and pericyte coverage. Interpretation We identified common variants near FOXF2 that are associated with increased stroke susceptibility. Epidemiological and experimental data suggest that FOXF2 mediates this association, potentially via differentiation defects of cerebral vascular mural cells. Further expression studies in appropriate human tissues, and further functional experiments with long follow-up periods are needed to fully understand the underlying mechanisms.

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Section: Methodsmentioning

confidence: 99%

Identification of additional risk loci for stroke and small vessel disease: a meta-analysis of genome-wide association studies

Chauhan¹,

Arnold²,

Chu³

et al. 2016

The Lancet Neurology

135

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“…In zebrafish embryos and juveniles nkx3 . 2 expression can be detected in the jaw joint, around the anterior notochord and vertebrae, and in the proximal radials of the median fins [ 27 , 28 ].…”

Section: Introductionmentioning

confidence: 99%

The broad role of Nkx3.2 in the development of the zebrafish axial skeleton

et al. 2021

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The transcription factor Nkx3.2 (Bapx1) is an important chondrocyte maturation inhibitor. Previous Nkx3.2 knockdown and overexpression studies in non-mammalian gnathostomes have focused on its role in primary jaw joint development, while the function of this gene in broader skeletal development is not fully described. We generated a mutant allele of nkx3.2 in zebrafish with CRISPR/Cas9 and applied a range of techniques to characterize skeletal phenotypes at developmental stages from larva to adult, revealing loss of the jaw joint, fusions in bones of the occiput, morphological changes in the Weberian apparatus, and the loss or deformation of bony elements derived from basiventral cartilages of the vertebrae. Axial phenotypes are reminiscent of Nkx3.2 knockout in mammals, suggesting that the function of this gene in axial skeletal development is ancestral to osteichthyans. Our results highlight the broad role of nkx3.2 in zebrafish skeletal development and its context-specific functions in different skeletal elements.

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“…These data clearly indicate a role of Nkx3.2 in the mammalian axial skeleton beyond just the middle ear that is homologous to the non-mammalian primary jaw joint, and yet the function of this gene in the axial skeleton of non-mammals has not been investigated in detail. In zebrafish embryos and juveniles nkx3.2 expression can be detected in the anterior notochord, vertebrae, and median proximal radials (Arnold et al, 2015;Crotwell and Mabee, 2007).…”

Section: Introductionmentioning

confidence: 99%

The Broad Role of Nkx3.2 in the Development of the Zebrafish Axial Skeleton

Waldmann

Leyhr

Zhang

et al. 2020

Preprint

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The transcription factor Nkx3.2 (Bapx1) is an important chondrocyte maturation inhibitor. Previous Nkx3.2 knock-down and overexpression studies in non-mammalian gnathostomes have focused on its role in primary jaw joint development, while little is known about the function of this gene in broader skeletal development. We generated CRISPR/Cas9 knockout of nkx3.2 in zebrafish and applied a range of techniques to characterize skeletal phenotypes at developmental stages from larva to adult, revealing fusions in bones of the occiput, the loss or deformation of bony elements derived from basiventral cartilages of the vertebrae, and an increased length of the proximal radials of the dorsal and anal fins. These phenotypes are reminiscent of Nkx3.2 knockout phenotypes in mammals, suggesting that the function of this gene in axial skeletal development is ancestral to osteichthyans. Our results highlight the broad role of nkx3.2 in zebrafish skeletal development and its context-specific functions in different skeletal elements.

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Comparative analysis of genes regulated by Dzip1/iguana and hedgehog in zebrafish

Cited by 19 publications

References 62 publications

Identification of additional risk loci for stroke and small vessel disease: a meta-analysis of genome-wide association studies

Identification of additional risk loci for stroke and small vessel disease: a meta-analysis of genome-wide association studies

The broad role of Nkx3.2 in the development of the zebrafish axial skeleton

The Broad Role of Nkx3.2 in the Development of the Zebrafish Axial Skeleton

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