tmem33 is essential for VEGF-mediated endothelial calcium oscillations and angiogenesis

Savage, Aaron M; Kurusamy, Sathishkumar; Chen, Yan; Jiang, Zhen; Chhabria, Karishma; Macdonald, R.; Kim, Hyejeong R.; Wilson, Heather L.; Eeden, Fredericus J.M. van; Armesilla, Ángel Luis; Chico, Timothy J. A.; Wilkinson, Robert N.

doi:10.1038/s41467-019-08590-7

Cited by 73 publications

(71 citation statements)

References 72 publications

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“…The requirement for embryonic left-right signalling pathways in promoting directionality of 49 heart morphogenesis is well established, with asymmetric Nodal signalling playing a key role 50 5 regional ECM thickness in the heart tube we used live in vivo light-sheet microscopy to image 101 quadruple transgenic zebrafish embryos at 26 hours post fertilisation (hpf). 102 Tg(myl7:lifeActGFP); Tg(fli1a:AC-TagRFP); Tg(lft2BAC:Gal4FF); Tg(UAS:RFP) zebrafish 103 express actin-tagged GFP in the myocardium (Reischauer et al 2014) and actin-localised RFP 104 in the endothelium including the endocardium (Savage et al 2019), allowing visualisation of 105 the two tissue layers in the heart tube. The Tg(lft2BAC:Gal4FF); Tg(UAS:RFP) double 106 transgenic drives RFP in lefty2-expressing cells, which comprises the dorsal myocardium of 107 the heart tube at 26hpf ( Fig 1A and Fig S1) (Smith et al 2008;Baker et al 2008).…”

Section: Introduction 37mentioning

confidence: 99%

Asymmetric Hapln1a drives regionalised cardiac ECM expansion and promotes heart morphogenesis during zebrafish development

Derrick¹,

Sánchez-Posada²,

Hussein³

et al. 2019

Preprint

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16The mature vertebrate heart develops from a simple linear cardiac tube during early 17 development through a series of highly asymmetric morphogenetic processes including cardiac 18 looping and chamber ballooning. While the directionality of heart morphogenesis is partly 19 controlled by embryonic laterality signals, previous studies have suggested that these extrinsic 20 laterality cues interact with tissue-intrinsic signals in the heart to ensure robust asymmetric 21 cardiac morphogenesis. Using live in vivo imaging of zebrafish embryos we describe a left-22 sided, chamber-specific expansion of the extracellular matrix (ECM) between the myocardium 23 and endocardium at early stages of heart morphogenesis. We use Tomo-seq, a spatial 24 transcriptomic approach, to identify transient and regionalised expression of hyaluronan and 25 2 proteoglycan link protein 1a (hapln1a), encoding an ECM cross-linking protein, in the heart 26 tube prior to cardiac looping overlapping with regionalised ECM expansion. Loss-and gain-27 of-function experiments demonstrate that regionalised Hapln1a promotes heart morphogenesis 28 through regional modulation of ECM thickness in the heart tube. Finally, we show that while 29 induction of asymmetric hapln1a expression is independent of embryonic left-right 30 asymmetry, these laterality cues are required to orient the hapln1a-expressing cells 31 asymmetrically along the left-right axis of the heart tube. 32Together, we propose a model whereby laterality cues position hapln1a expression on the left 33 of the heart tube, and this asymmetric Hapln1a deposition drives ECM asymmetry and 34 subsequently promotes robust asymmetric cardiac morphogenesis. 35 36 in driving rightward looping of the linear heart tube in multiple organisms (Levin et al. 1995; 51 Lowe et al. 1996;Long 2003;Brennan et al. 2002;Toyoizumi et al. 2005). However, while 52 embryos with defective asymmetric Nodal signalling display disrupted directionality of heart 53 looping, the heart still undergoes looping morphogenesis (Noël et al. 2013; Brennan et al. 54 2002). This indicates that while extrinsic asymmetric cues provide directional information to 55 the heart, regionalised intrinsic signals help to promote asymmetric morphogenesis. Supporting 56

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Section: Introduction 37mentioning

confidence: 99%

Asymmetric Hapln1a drives regionalised cardiac ECM expansion and promotes heart morphogenesis during zebrafish development

Derrick¹,

Sánchez-Posada²,

Hussein³

et al. 2019

Preprint

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“…For example, an examination of kugel formation in stable mutants of these genes would be interesting although it may be challenging to discriminate between the effects of their loss of function on general cerebrovascular development. The recent establishment of endothelial-specific CRISPR interference may also be informative [47]. Our finding that the majority of kugeln contained high levels of NO was unexpected as NO is generally considered to passively diffuse from NO-producing cells and no NO-containing organelle has previously been described [48].…”

Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Cerebrovascular endothelial cells form transient Notch‐dependent cystic structures in zebrafish

Kugler

Lessen²,

Daetwyler

et al. 2019

EMBO Reports

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We identify a novel endothelial membrane behaviour in transgenic zebrafish. Cerebral blood vessels extrude large transient spherical structures that persist for an average of 23 min before regressing into the parent vessel. We term these structures “kugeln”, after the German for sphere. Kugeln are only observed arising from the cerebral vessels and are present as late as 28 days post fertilization. Kugeln do not communicate with the vessel lumen and can form in the absence of blood flow. They contain little or no cytoplasm, but the majority are highly positive for nitric oxide reactivity. Kugeln do not interact with brain lymphatic endothelial cells (BLECs) and can form in their absence, nor do they perform a scavenging role or interact with macrophages. Inhibition of actin polymerization, Myosin II, or Notch signalling reduces kugel formation, while inhibition of VEGF or Wnt dysregulation (either inhibition or activation) increases kugel formation. Kugeln represent a novel Notch‐dependent NO‐containing endothelial organelle restricted to the cerebral vessels, of currently unknown function.

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“…Here, the zebrafish holds promise as a model system, partly because the otoliths are a highly visible proxy readout of ciliary integrity. As technologies to achieve tissue-specific disruption of zebrafish gene function improve (see, for example, (Kirchgeorg et al, 2018;Savage et al, 2019; Cilia in the zebrafish ear are also interesting in their own right; key among the problems remaining to be solved is an understanding of the unique protein or lipid composition at the tip of the tether kinocilium that distinguishes it from other cilia, allowing otolith precursor particles to bind there so precisely and robustly. Comparison of the rotational motile cilia in the otic vesicle to those in Kupffer's vesicle or the floorplate may also lead to general insights into mechanisms of cilia-driven flow and its consequences for developmental patterning.…”

Section: Resultsmentioning

confidence: 99%

Cilia in the developing zebrafish ear

Whitfield

2019

Phil. Trans. R. Soc. B

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The inner ear, which mediates the senses of hearing and balance, derives from a simple ectodermal vesicle in the vertebrate embryo. In the zebrafish, the otic placode and vesicle express a whole suite of genes required for ciliogenesis and ciliary motility. Every cell of the otic epithelium is ciliated at early stages; at least three different ciliary subtypes can be distinguished on the basis of length, motility, genetic requirements and function. In the early otic vesicle, most cilia are short and immotile. Long, immotile kinocilia on the first sensory hair cells tether the otoliths, biomineralized aggregates of calcium carbonate and protein. Small numbers of motile cilia at the poles of the otic vesicle contribute to the accuracy of otolith tethering, but neither the presence of cilia nor ciliary motility is absolutely required for this process. Instead, otolith tethering is dependent on the presence of hair cells and the function of the glycoprotein Otogelin. Otic cilia or ciliary proteins also mediate sensitivity to ototoxins and coordinate responses to extracellular signals. Other studies are beginning to unravel the role of ciliary proteins in cellular compartments other than the kinocilium, where they are important for the integrity and survival of the sensory hair cell. This article is part of the Theo Murphy meeting issue ‘Unity and diversity of cilia in locomotion and transport’.

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tmem33 is essential for VEGF-mediated endothelial calcium oscillations and angiogenesis

Cited by 73 publications

References 72 publications

Asymmetric Hapln1a drives regionalised cardiac ECM expansion and promotes heart morphogenesis during zebrafish development

Asymmetric Hapln1a drives regionalised cardiac ECM expansion and promotes heart morphogenesis during zebrafish development

Cerebrovascular endothelial cells form transient Notch‐dependent cystic structures in zebrafish

Cilia in the developing zebrafish ear

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