<i>mafba</i> is a downstream transcriptional effector of Vegfc signaling essential for embryonic lymphangiogenesis in zebrafish

Koltowska, Katarzyna; Paterson, Scott; Bower, Neil I.; Baillie, Gregory J.; Lagendijk, Anne Karine; Astin, Jonathan W.; Chen, Huijun; François, Mathias; Crosier, Philip S.; Taft, Ryan J.; Simons, Cas; Smith, K. A.; Hogan, Benjamin M.

doi:10.1101/gad.263210.115

Cited by 64 publications

(86 citation statements)

References 77 publications

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“…The Notch1 probe was generated by PCR from mouse embryo cDNA pool at E14.5, and reverse transcribed with T7 polymerase. Whole-mount immunohistochemistry for anti-GFP was performed as described (Koltowska et al, 2015). For details, see the supplementary Materials and Methods.…”

Section: In Situ Hybridisation and Immunofluorescence Stainingmentioning

confidence: 99%

SoxF factors induce Notch1 expression via direct transcriptional regulation during early arterial development

et al. 2017

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Arterial specification and differentiation are influenced by a number of regulatory pathways. While it is known that the Vegfa-Notch cascade plays a central role in this biological process, the transcriptional hierarchy controlling arterial specification has not been fully delineated. To elucidate the direct transcriptional regulators of Notch receptor expression in arterial endothelial cells, we used histone signatures, DNaseI hypersensitivity and ChIP-seq data to identify enhancers for the human NOTCH1 and zebrafish notch1b genes. These enhancers were able to direct arterial endothelial cell-restricted expression in transgenic models. Genetic disruption of SOXF binding sites clearly established a requirement for members of the SOXF group of transcription factors (SOX7,-17 and-18) to drive these enhancers activity in vivo. Further, endogenous deletion of the notch1b enhancer led to a significant augmentation of arterio-venous defects in notch-pathway deficient zebrafish. Loss of SoxF function revealed that these factors are necessary for the activity of NOTCH1 and notch1b enhancers, and for correct endogenous Notch1 gene transcription. These findings therefore position SOXF transcription factors directly upstream of Notch receptor expression during the acquisition of arterial identity in vertebrates.

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Section: In Situ Hybridisation and Immunofluorescence Stainingmentioning

confidence: 99%

SoxF factors induce Notch1 expression via direct transcriptional regulation during early arterial development

et al. 2017

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“…Mafba was reported to be important for the initial migration of LECs, following their sprouting from the PCV, in a cell-autonomous manner (Koltowska et al, 2015b). In addition, Mafb has been shown to be important for lymphatic sprouting in mice (Dieterich et al, 2015).…”

Section: Molecular Mechanisms Controlling Lymphatic Sprouting and Migmentioning

confidence: 99%

“…In addition to its established role in promoting LEC sprouting through binding of the Vegfr3 receptor, Vegfc signaling was recently shown to regulate the levels of mafba, which encodes a transcription factor involved in lymphatic development in zebrafish (Koltowska et al, 2015b). Mafba was reported to be important for the initial migration of LECs, following their sprouting from the PCV, in a cell-autonomous manner (Koltowska et al, 2015b).…”

Section: Molecular Mechanisms Controlling Lymphatic Sprouting and Migmentioning

confidence: 99%

Development of the lymphatic system: new questions and paradigms

2016

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The lymphatic system is a blind-ended network of vessels that plays important roles in mediating tissue fluid homeostasis, intestinal lipid absorption and the immune response. A profound understanding of the development of lymphatic vessels, as well as of the molecular cues governing their formation and morphogenesis, might prove essential for our ability to treat lymphatic-related diseases. The embryonic origins of lymphatic vessels have been debated for over a century, with a model claiming a venous origin for the lymphatic endothelium being predominant. However, recent studies have provided new insights into the origins of lymphatic vessels. Here, we review the molecular mechanisms controlling lymphatic specification and sprouting, and we discuss exciting findings that shed new light on previously uncharacterized sources of lymphatic endothelial cells.

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“…Recent work has revealed some initial guidance cues directing lymphangiogenesis. [11][12][13][14][15] For instance, chemokine (C-X-C motif) ligand (Cxcl12a) guides Cxcr4a/b-expressing LECs extension along HM to form PLs and Cxcl12b-Cxcr4a/b signaling, after which it directs dorsoventral growth of PL-derived lymphatic sprouts along arterial intersegmental vessel (ISV). 15 However, the regulator of Cxcl12a/b expression and the mechanisms directing lymphangiogenesis presently remain undefined.…”

Section: Arterioscler Thromb Vasc Biolmentioning

confidence: 99%

MicroRNA-126a Directs Lymphangiogenesis Through Interacting With Chemokine and Flt4 Signaling in Zebrafish

Chen

Zhu

et al. 2016

ATVB

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Objective— MicroRNA-126 (miR-126) is an endothelium-enriched miRNA and functions in vascular integrity and angiogenesis. The application of miRNA as potential biomarker and therapy target has been widely investigated in various pathological processes. However, its role in lymphatic diseases had not been widely explored. We aimed to reveal the role of miR-126 in lymphangiogenesis and the regulatory signaling pathways for potential targets of therapy. Approach and Results— Loss-of-function studies using morpholino oligonucleotides and CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9) system showed that silencing of miR-126a severely affected the formation of parachordal lymphangioblasts and thoracic duct in zebrafish embryos, although their development in miR-126b knockdown embryos was normal. Expression analyses by in situ hybridization and immunofluorescence indicated that miR-126a was expressed in lymphatic vessels, as well as in blood vessels. Time-lapse confocal imaging assay further revealed that knockdown of miR-126a blocked both lymphangiogenic sprouts budding from the posterior cardinal vein and lymphangioblasts extension along horizontal myoseptum. Bioinformatics analysis and in vivo report assay identified that miR-126a upregulated Cxcl12a by targeting its 5′ untranslated region. Moreover, loss- and gain-of-function studies revealed that Cxcl12a signaling acted downstream of miR-126a during parachordal lymphangioblast extension, whereby Flt4 signaling acts as a cooperator of miR-126a, allowing it to modulate lymphangiogenic sprout formation. Conclusions— These findings demonstrate that miR-126a directs lymphatic endothelial cell sprouting and extension by interacting with Cxcl12a-mediated chemokine signaling and Vegfc-Flt4 signal axis. Our results suggest that these key regulators of lymphangiogenesis may be involved in lymphatic pathogenesis of cardiovascular diseases.

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mafba is a downstream transcriptional effector of Vegfc signaling essential for embryonic lymphangiogenesis in zebrafish

Cited by 64 publications

References 77 publications

SoxF factors induce Notch1 expression via direct transcriptional regulation during early arterial development

SoxF factors induce Notch1 expression via direct transcriptional regulation during early arterial development

Development of the lymphatic system: new questions and paradigms

MicroRNA-126a Directs Lymphangiogenesis Through Interacting With Chemokine and Flt4 Signaling in Zebrafish

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