Bone Morphogenetic Protein 2 Signaling Negatively Modulates Lymphatic Development in Vertebrate Embryos

Dunworth, William P.; Cardona-Costa, J.; Çağavı, Esra; Kim, Jun Dae; Meadows, Stryder M.; Fischer, Johanna C.; Wang, Yeqi; Cleaver, Ondine; Qyang, Yibing; Ober, Elke A.; Jin, Suk Won

doi:10.1161/circresaha.114.302452

Cited by 87 publications

(96 citation statements)

References 76 publications

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“…reported that Bmp suppresses the expression of Prox1, a key regulator of lymphatic development, thereby preventing differentiation of lymphatic ECs (Dunworth et al, 2014). As such, Bmp might regulate venous vessel formation by inducing the differentiation of venous ECs through expression of Nr2f2 and by suppressing the differentiation of lymphatic ECs through downregulation of Prox1.…”

Section: Discussionmentioning

confidence: 99%

β-catenin-dependent transcription is central to Bmp-mediated formation of venous vessels

et al. 2015

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β-catenin regulates the transcription of genes involved in diverse biological processes, including embryogenesis, tissue homeostasis and regeneration. Endothelial cell (EC)-specific gene-targeting analyses in mice have revealed that β-catenin is required for vascular development. However, the precise function of β-cateninmediated gene regulation in vascular development is not well understood, since β-catenin regulates not only gene expression but also the formation of cell-cell junctions. To address this question, we have developed a novel transgenic zebrafish line that allows the visualization of β-catenin transcriptional activity specifically in ECs and discovered that β-catenin-dependent transcription is central to the bone morphogenetic protein (Bmp)-mediated formation of venous vessels. During caudal vein (CV) formation, Bmp induces the expression of aggf1, a putative causative gene for KlippelTrenaunay syndrome, which is characterized by venous malformation and hypertrophy of bones and soft tissues. Subsequently, Aggf1 potentiates β-catenin transcriptional activity by acting as a transcriptional co-factor, suggesting that Bmp evokes β-catenin-mediated gene expression through Aggf1 expression. Bmp-mediated activation of β-catenin induces the expression of Nr2f2 (also known as Coup-TFII), a member of the nuclear receptor superfamily, to promote the differentiation of venous ECs, thereby contributing to CV formation. Furthermore, β-catenin stimulated by Bmp promotes the survival of venous ECs, but not that of arterial ECs. Collectively, these results indicate that Bmp-induced activation of β-catenin through Aggf1 regulates CV development by promoting the Nr2f2-dependent differentiation of venous ECs and their survival. This study demonstrates, for the first time, a crucial role of β-catenin-mediated gene expression in the development of venous vessels.

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Section: Discussionmentioning

confidence: 99%

β-catenin-dependent transcription is central to Bmp-mediated formation of venous vessels

et al. 2015

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“…To date, no animal knockout models are available for miR-31 and limited studies have been conducted to understand the function of miR-31 in the context of embryogenesis (Schuldt, 2005;Dunworth et al, 2014). To identify the function of miR-31 in the developing embryo, we used the purple sea urchin Strongylocentrotus purpuratus as a model.…”

Section: Introductionmentioning

confidence: 99%

microRNA-31 modulates skeletal patterning in the sea urchin embryos

Stepicheva

Song

2015

Development

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MicroRNAs (miRNAs) are small non-coding RNAs that repress the translation and reduce the stability of target mRNAs in animal cells. microRNA-31 (miR-31) is known to play a role in cancer, bone formation and lymphatic development. However, studies to understand the function of miR-31 in embryogenesis have been limited. We examined the regulatory role of miR-31 in early development using the sea urchin as a model. miR-31 is expressed at all stages of development and its knockdown (KD) disrupts the patterning and function of primary mesenchyme cells (PMCs), which form the embryonic skeleton spicules. We identified that miR-31 directly represses Pmar1, Alx1, Snail and VegfR7 within the PMC gene regulatory network using reporter constructs. Further, blocking the miR-31-mediated repression of Alx1 and/or VegfR7 in the developing embryo resulted in defects in PMC patterning and skeletogenesis. The majority of the mislocalized PMCs in miR-31 KD embryos did not express VegfR10, indicating that miR-31 regulates VegfR gene expression within PMCs. In addition, miR-31 indirectly suppresses Vegf3 expression in the ectoderm. These results indicate that miR-31 coordinately suppresses genes within the PMCs and in the ectoderm to impact PMC patterning and skeletogenesis. This study identifies the novel function and molecular mechanism of miR-31-mediated regulation in the developing embryo.

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“…While antiangiogenic BMP9/Alk1 signaling promotes lymphatic development Levet=et al, 2013), pro-angiogenic BMP2/Alk2/3 signaling inhibits lymphatic development (Dunworth=et al, 2013;Kim=et al, 2012;Wiley=et al, 2011), suggesting distinct cellular responses toward BMP signaling in BECs and LECs. In addition, transforming growth factor β (TGFβ), a signaling ligand related to BMPs, appears to provide contextdependent regulation of lymphatic development.…”

Section: Molecular Mechanisms Modulating Development Of the Lymphaticmentioning

confidence: 99%

“…Transgenic lines which express fluorescent reporters under vascular specific promoters such as îÉÖÑêO/âÇêä (Jin= et al, 2005), ÑäáN~ (Lawson and Weinstein, 2002) and ÉíîO/Éíëêé (Kohli=et al, 2013), have been generated. More recently, two lymphatic specific transgenic lines have been generated which express fluorescent reporters under éêçñN~ or äóîÉN promoters (Dunworth et al, 2013;Okuda et al, 2012).…”

Section: Transient and Permanent Genetic Manipulation In Zebrafish Emmentioning

confidence: 99%

A Tale of Two Models: Mouse and Zebrafish as Complementary Models for Lymphatic Studies

Kim¹,

Jin²

2014

Molecules and Cells

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Lymphatic vessels provide essential roles in maintaining fluid homeostasis and lipid absorption. Dysfunctions of the lymphatic vessels lead to debilitating pathological conditions, collectively known as lymphedema. In addition, lymphatic vessels are a critical moderator for the onset and progression of diverse human diseases including metastatic cancer and obesity. Despite their clinical importance, there is no currently effective pharmacological therapy to regulate functions of lymphatic vessels. Recent efforts to manipulate the Vascular Endothelial Growth Factor-C (VEGFC) pathway, which is arguably the most important signaling pathway regulating lymphatic endothelial cells, to alleviate lymphedema yielded largely mixed results, necessitating identification of new targetable signaling pathways for therapeutic intervention for lymphedema. Zebrafish, a relatively new model system to investigate lymphatic biology, appears to be an ideal model to identify novel therapeutic targets for lymphatic biology. In this review, we will provide an overview of our current understanding of the lymphatic vessels in vertebrates, and discuss zebrafish as a promising in vivo model to study lymphatic vessels.

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Bone Morphogenetic Protein 2 Signaling Negatively Modulates Lymphatic Development in Vertebrate Embryos

Cited by 87 publications

References 76 publications

β-catenin-dependent transcription is central to Bmp-mediated formation of venous vessels

β-catenin-dependent transcription is central to Bmp-mediated formation of venous vessels

microRNA-31 modulates skeletal patterning in the sea urchin embryos

A Tale of Two Models: Mouse and Zebrafish as Complementary Models for Lymphatic Studies

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