Development of the brain vasculature and the blood-brain barrier in zebrafish

Quiñonez-Silvero, Claudia; Hübner, Kathleen; Herzog, Wiebke

doi:10.1016/j.ydbio.2019.03.005

Cited by 80 publications

(57 citation statements)

References 125 publications

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“…Vascular expression levels for mfsd2aa or mfsd2ab were then background corrected using the measurements from the Gfap probe. As a positive control, we also performed FISH for the BBB-specific vascular marker slc2a1a (also known as glut1b ) (Umans et al, 2017; Quiñonez-Silvero et al, 2019), and observed consistent slc2a1a signal in cerebral vessels at all time points examined (Figure 4—figure supplement 1). FISH revealed undetectable levels of mfsd2aa expression in cerebral vessels at 3 dpf, higher levels at 5 dpf, when BBB endothelial cells suppress transcytosis (Figure 3), and intermediate levels in adult blood vessels (Figure 4).…”

Section: Resultsmentioning

confidence: 82%

“…As the simplest genetic model organism with an endothelial BBB (Jeong et al, 2008), zebrafish offer a powerful tool to study the cellular and molecular properties of the vertebrate BBB (Xie et al, 2010; Vanhollebeke et al, 2015; Umans et al, 2017; O'Brown et al, 2018; Quiñonez-Silvero et al, 2019). Zebrafish have served as a great model system to study vascular biology due to their large clutch size, rapid and external development, and transparency for in vivo whole organism live-imaging (Lawson and Weinstein, 2002; Jin et al, 2005; Santoro et al, 2007; Armer et al, 2009; Herbert et al, 2009; Phng et al, 2009; Geudens et al, 2010; Herbert et al, 2012; Wilkinson and van Eeden, 2014; Franco et al, 2015; Vanhollebeke et al, 2015; Matsuoka et al, 2016; Ulrich et al, 2016; Venero Galanternik et al, 2017; Stratman et al, 2017; Geudens et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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Suppression of transcytosis regulates zebrafish blood-brain barrier function

O'Brown

Megason

2019

eLife

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As an optically transparent model organism with an endothelial blood-brain barrier (BBB), zebrafish offer a powerful tool to study the vertebrate BBB. However, the precise developmental profile of functional zebrafish BBB acquisition and the subcellular and molecular mechanisms governing the zebrafish BBB remain poorly characterized. Here, we capture the dynamics of developmental BBB leakage using live imaging, revealing a combination of steady accumulation in the parenchyma and sporadic bursts of tracer leakage. Electron microscopy studies further reveal high levels of transcytosis in brain endothelium early in development that are suppressed later. The timing of this suppression of transcytosis coincides with the establishment of BBB function. Finally, we demonstrate a key mammalian BBB regulator Mfsd2a, which inhibits transcytosis, plays a conserved role in zebrafish, as mfsd2aa mutants display increased BBB permeability due to increased transcytosis. Our findings indicate a conserved developmental program of barrier acquisition between zebrafish and mice.

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Section: Resultsmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Suppression of transcytosis regulates zebrafish blood-brain barrier function

O'Brown

Megason

2019

eLife

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“…throughout the entire body in vivo at high resolution. Moreover, the development, structure and function of the BBB being conserved between mammals and zebrafish, this model provides a means to test the permeability of the BBB to ML [21][22][23]. Here, we used a fluorescent surrogate of ML [24][25][26] and a combination of in vitro and in vivo approaches to investigate the spatiotemporal distribution of ML at the whole-organism scale and address the critical question of its access to the brain.…”

Section: Introductionmentioning

confidence: 99%

Spatiotemporal analysis of mycolactone distribution in vivo reveals partial diffusion in the central nervous system

et al. 2020

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Mycobacterium ulcerans, the causative agent of Buruli ulcer (BU) disease, is unique amongst human pathogens in its capacity to produce a lipid toxin called mycolactone. While previous studies have demonstrated that bacterially-released mycolactone diffuses beyond infection foci, the spatiotemporal distribution of mycolactone remained largely unknown. Here, we used the zebrafish model to provide the first global kinetic analysis of mycolactone’s diffusion in vivo, and multicellular co-culture systems to address the critical question of the toxin’s access to the brain. Zebrafish larvae were injected with a fluorescent-derivative of mycolactone to visualize the in vivo diffusion of the toxin from the peripheral circulation. A rapid, body-wide distribution of mycolactone was observed, with selective accumulation in tissues near the injection site and brain, together with an important excretion through the gastro-intestinal tract. Our conclusion that mycolactone reached the central nervous system was reinforced by an in cellulo model of human blood brain barrier and a mouse model of M. ulcerans-infection. Here we show that mycolactone has a broad but heterogenous profile of distribution in vivo. Our investigations in vitro and in vivo support the view that a fraction of bacterially-produced mycolactone gains access to the central nervous system. The relative persistence of mycolactone in the bloodstream suggests that assays of circulating mycolactone are relevant for BU disease monitoring and treatment optimization.

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“…mSOD1 larvae were treated with a single or combined drugs once the BBB was fully developed. 46 In this experiment, a clear synergistic effect was evident between the drugs. However, due to constraints of injected-mRNA stability, mTDP-43 larval experiments ª 2020 The Authors.…”

Section: Discussionmentioning

confidence: 56%

Efficacy of Ciprofloxacin/Celecoxib combination in zebrafish models of amyotrophic lateral sclerosis

Goldshtein

Muhire

Légaré

et al. 2020

Ann Clin Transl Neurol

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Objective: To evaluate the efficacy of a fixed-dose combination of two approved drugs, Ciprofloxacin and Celecoxib, as a potential therapeutic treatment for amyotrophic lateral sclerosis (ALS). Methods: Toxicity and efficacy of Ciprofloxacin and Celecoxib were tested, each alone and in distinct ratio combinations in SOD1 G93R transgenic zebrafish model for ALS. Quantification of swimming measures following stimuli, measurements of axonal projections from the spinal cord, neuromuscular junction structure and morphometric analysis of microglia cells were performed in the combination-treated vs nontreated mutant larvae. Additionally, quantifications of touch-evoked locomotor escape response were conducted in treated vs nontreated zebrafish expressing the TARDBP G348C ALS variant. Results: When administered individually, Ciprofloxacin had a mild effect and Celecoxib had no therapeutic effect. However, combined Ciprofloxacin and Celecoxib (Cipro/Celecox) treatment caused a significant increase of~84% in the distance the SOD1 G93R transgenic larvae swam. Additionally, Cipro/Celecox elicited recovery of impaired motor neurons morphology and abnormal neuromuscular junction structure and preserved the ramified morphology of microglia cells in the SOD1 mutants. Furthermore, larvae expressing the TDP-43 mutation displayed evoked touch responses that were significantly longer in swim distance (110% increase) and significantly higher in maximal swim velocity (~44% increase) when treated with Cipro/Celecox combination. Interpretation: Cipro/Celecox combination improved locomotor and cellular deficits of ALS zebrafish models. These results identify this novel combination as effective, and may prove promising for the treatment of ALS.

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Development of the brain vasculature and the blood-brain barrier in zebrafish

Cited by 80 publications

References 125 publications

Suppression of transcytosis regulates zebrafish blood-brain barrier function

Suppression of transcytosis regulates zebrafish blood-brain barrier function

Spatiotemporal analysis of mycolactone distribution in vivo reveals partial diffusion in the central nervous system

Efficacy of Ciprofloxacin/Celecoxib combination in zebrafish models of amyotrophic lateral sclerosis

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