ccbe1 is required for embryonic lymphangiogenesis and venous sprouting

Hogan, Benjamin M.; Bos, Frank L.; Bussmann, Jeroen; Witte, Merlijn; Neil, C.; Duckers, Hendricus J.; Schulte‐Merker, Stefan

doi:10.1038/ng.321

Cited by 437 publications

(583 citation statements)

References 14 publications

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“…3 C and D). Next, to test whether the dn-Vegfaa isoform might affect Vegfc signaling, we heatshocked Tg(hsp70l:dn-vegfaa) and WT clutchmates at 30 hpf, before the onset of secondary sprouting, a well-documented vegfc-dependent process (33). Embryos received a 1-h heatshock every 12 h until 5 dpf.…”

Section: Resultsmentioning

confidence: 99%

Fast revascularization of the injured area is essential to support zebrafish heart regeneration

Marín-Juez

Marass

Gauvrit

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

164

222

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Zebrafish have a remarkable capacity to regenerate their heart. Efficient replenishment of lost tissues requires the activation of different cell types including the epicardium and endocardium. A complex set of processes is subsequently needed to support cardiomyocyte repopulation. Previous studies have identified important determinants of heart regeneration; however, to date, how revascularization of the damaged area happens remains unknown. Here, we show that angiogenic sprouting into the injured area starts as early as 15 h after injury. To analyze the role of vegfaa in heart regeneration, we used vegfaa mutants rescued to adulthood by vegfaa mRNA injections at the one-cell stage. Surprisingly, vegfaa mutants develop coronaries and revascularize after injury. As a possible explanation for these observations, we find that vegfaa mutant hearts up-regulate the expression of potentially compensating genes. Therefore, to overcome the lack of a revascularization phenotype in vegfaa mutants, we generated fish expressing inducible dominant negative Vegfaa. These fish displayed minimal revascularization of the damaged area. In the absence of fast angiogenic revascularization, cardiomyocyte proliferation did not occur, and the heart failed to regenerate, retaining a fibrotic scar. Hence, our data show that a fast endothelial invasion allows efficient revascularization of the injured area, which is necessary to support replenishment of new tissue and achieve efficient heart regeneration. These findings revisit the model where neovascularization is considered to happen concomitant with the formation of new muscle. Our work also paves the way for future studies designed to understand the molecular mechanisms that regulate fast revascularization.heart regeneration | angiogenesis | revascularization | coronaries | VEGF

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Section: Resultsmentioning

confidence: 99%

Fast revascularization of the injured area is essential to support zebrafish heart regeneration

Marín-Juez

Marass

Gauvrit

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

164

222

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“…Tg(fli1a:EGFP) y1 , Tg(fli1a:nEGFP) y7 , Tg(kdrl:hras-mcherry) s896 ; Tg(flt1 BAC :yfp), transgenic zebrafish lines were used as described. [20][21][22][23][24] To knockdown gene expression in zebrafish embryos, we used a morpholino (small antisense molecules capable of blocking mRNA translation or splicing) approach. Morpholinos (GeneTools; sequences in Table S1 in the online-only Data Supplement), and miRNA precursors (Ambion) were injected at the 1 to 2 cell stage.…”

Section: Methodsmentioning

confidence: 99%

miR-30a Regulates Endothelial Tip Cell Formation and Arteriolar Branching

et al. 2013

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Microvascular rarefaction increases vascular resistance and pressure in systemic arteries and is a hallmark of fixed essential hypertension. Preventing rarefaction by activation of angiogenic processes could lower blood pressure. Endothelial tip cells in angiogenic sprouts direct branching of microvascular networks; the process is regulated by microRNAs, particularly the miR-30 family. We investigated the contribution of miR-30 family members in arteriolar branching morphogenesis via delta-like 4 (Dll4)-Notch signaling in a zebrafish model. The miR-30 family consists of 5 members (miR-30a-e). Loss-of-function experiments showed that only miR-30a reduced growth of intersegmental arterioles involving impaired tip cell function. Overexpression of miR-30a stimulated tip cell behavior resulting in augmented branching of intersegmental arterioles. In vitro and in vivo reporter assays showed that miR-30a directly targets the Notch ligand Dll4, a key inhibitor of tip cell formation. Coadministration of a Dll4 targeting morpholino in miR-30a morphants rescued the branching defects. Conversely, conditional overexpression of Notch intracellular domain restored arteriolar branching in miR-30a gain-of-function embryos. In human endothelial cells, loss of miR-30a increased DLL4 protein levels, activated Notch signaling as indicated in Notch reporter assays, and augmented Notch downstream effector, HEY2 and EFNB2 (ephrin-B2), expression. In spheroid assays, miR-30a loss- and gain-of-function affected tip cell behavior, consistent with miR-30a targeting Dll4. Our data suggest that miR-30a stimulates arteriolar branching by downregulating endothelial Dll4 expression, thereby controlling endothelial tip cell behavior. These findings could have relevance to the rarefaction process and, therefore, to hypertension.

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“…The GJC2 gene encodes connexin 47, an intercellular gap junction protein, and mutations in the protein were postulated to cause impaired gap junction activities and result in defective lymphatic flow (Ferrell et al 2010). CCBE1 has been shown to play a role in lymphatic sprouting during zebrafish development, and mutations in CCBE1 were found in patients with Hennekam lymphangiectasia -lymphedema syndrome (Alders et al 2009;Hogan et al 2009). …”

Section: Primary Lymphedemamentioning

confidence: 99%

The New Era of the Lymphatic System: No Longer Secondary to the Blood Vascular System

Choi

Lee²,

Hong

2012

Cold Spring Harbor Perspectives in Medicine

118

107

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The blood and lymphatic systems are the two major circulatory systems in our body. Although the blood system has been studied extensively, the lymphatic system has received much less scientific and medical attention because of its elusive morphology and mysterious pathophysiology. However, a series of landmark discoveries made in the past decade has begun to change the previous misconception of the lymphatic system to be secondary to the more essential blood vascular system. In this article, we review the current understanding of the development and pathology of the lymphatic system. We hope to convince readers that the lymphatic system is no less essential than the blood circulatory system for human health and well-being.

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ccbe1 is required for embryonic lymphangiogenesis and venous sprouting

Cited by 437 publications

References 14 publications

Fast revascularization of the injured area is essential to support zebrafish heart regeneration

Fast revascularization of the injured area is essential to support zebrafish heart regeneration

miR-30a Regulates Endothelial Tip Cell Formation and Arteriolar Branching

The New Era of the Lymphatic System: No Longer Secondary to the Blood Vascular System

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