Venous identity requires BMP signalling through ALK3

Alice Neal; Svanhild Nornes; Sophie Payne; Marsha D Wallace; Martin Fritzsche; Pakavarin Louphrasitthiphol; Robert N Wilkinson; Kira M Chouliaras; Ke Liu; Karen Plant; Radhika Sholapurkar; Indrika Ratnayaka; Wiebke Herzog; Gareth Bond; Tim Chico; George Bou-Gharios; Sarah De Val

doi:10.1038/s41467-019-08315-w

Venous identity requires BMP signalling through ALK3

Alice Neal, Svanhild Nornes, Sophie Payne, Marsha D Wallace, Martin Fritzsche, Pakavarin Louphrasitthiphol, Robert N Wilkinson, Kira M Chouliaras, Ke Liu, Karen Plant, Radhika Sholapurkar, Indrika Ratnayaka, Wiebke Herzog, Gareth Bond, Tim Chico, George Bou-Gharios, Sarah De Val

Cancer and Genomic Sciences

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Abstract

Venous endothelial cells are molecularly and functionally distinct from their arterial counterparts. Although veins are often considered the default endothelial state, genetic manipulations can modulate both acquisition and loss of venous fate, suggesting that venous identity is the result of active transcriptional regulation. However, little is known about this process. Here we show that BMP signalling controls venous identity via the ALK3/BMPR1A receptor and SMAD1/SMAD5. Perturbations to TGF-β and BMP signalling in mice and zebrafish result in aberrant vein formation and loss of expression of the venous-specific gene Ephb4, with no effect on arterial identity. Analysis of a venous endothelium-specific enhancer for Ephb4 shows enriched binding of SMAD1/5 and a requirement for SMAD binding motifs. Further, our results demonstrate that BMP/SMAD-mediated Ephb4 expression requires the venous-enriched BMP type I receptor ALK3/BMPR1A. Together, our analysis demonstrates a requirement for BMP signalling in the establishment of Ephb4 expression and the venous vasculature.

Original language	English
Article number	453
Pages (from-to)	1-18
Number of pages	18
Journal	Nature Communications
Volume	10
DOIs	https://doi.org/10.1038/s41467-019-08315-w
Publication status	Published - 28 Jan 2019

Keywords

Animals
Animals, Genetically Modified
Bone Morphogenetic Protein Receptors, Type I/genetics
Bone Morphogenetic Proteins/genetics
Endothelial Cells/metabolism
Gene Expression Regulation, Developmental
Mice, Knockout
Mice, Transgenic
Receptor, EphB4/genetics
Signal Transduction/genetics
Smad1 Protein/genetics
Smad5 Protein/genetics
Transforming Growth Factor beta/genetics
Veins/embryology
Zebrafish/embryology
Zebrafish Proteins/genetics

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Neal, A., Nornes, S., Payne, S., Wallace, M. D., Fritzsche, M., Louphrasitthiphol, P., Wilkinson, R. N., Chouliaras, K. M., Liu, K., Plant, K., Sholapurkar, R., Ratnayaka, I., Herzog, W., Bond, G., Chico, T., Bou-Gharios, G., & De Val, S. (2019). Venous identity requires BMP signalling through ALK3. Nature Communications, 10, 1-18. Article 453. https://doi.org/10.1038/s41467-019-08315-w

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abstract = "Venous endothelial cells are molecularly and functionally distinct from their arterial counterparts. Although veins are often considered the default endothelial state, genetic manipulations can modulate both acquisition and loss of venous fate, suggesting that venous identity is the result of active transcriptional regulation. However, little is known about this process. Here we show that BMP signalling controls venous identity via the ALK3/BMPR1A receptor and SMAD1/SMAD5. Perturbations to TGF-β and BMP signalling in mice and zebrafish result in aberrant vein formation and loss of expression of the venous-specific gene Ephb4, with no effect on arterial identity. Analysis of a venous endothelium-specific enhancer for Ephb4 shows enriched binding of SMAD1/5 and a requirement for SMAD binding motifs. Further, our results demonstrate that BMP/SMAD-mediated Ephb4 expression requires the venous-enriched BMP type I receptor ALK3/BMPR1A. Together, our analysis demonstrates a requirement for BMP signalling in the establishment of Ephb4 expression and the venous vasculature.",

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AU - Fritzsche, Martin

AU - Louphrasitthiphol, Pakavarin

AU - Wilkinson, Robert N

AU - Chouliaras, Kira M

AU - Liu, Ke

AU - Plant, Karen

AU - Sholapurkar, Radhika

AU - Ratnayaka, Indrika

AU - Herzog, Wiebke

AU - Bond, Gareth

AU - Chico, Tim

AU - Bou-Gharios, George

AU - De Val, Sarah

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N2 - Venous endothelial cells are molecularly and functionally distinct from their arterial counterparts. Although veins are often considered the default endothelial state, genetic manipulations can modulate both acquisition and loss of venous fate, suggesting that venous identity is the result of active transcriptional regulation. However, little is known about this process. Here we show that BMP signalling controls venous identity via the ALK3/BMPR1A receptor and SMAD1/SMAD5. Perturbations to TGF-β and BMP signalling in mice and zebrafish result in aberrant vein formation and loss of expression of the venous-specific gene Ephb4, with no effect on arterial identity. Analysis of a venous endothelium-specific enhancer for Ephb4 shows enriched binding of SMAD1/5 and a requirement for SMAD binding motifs. Further, our results demonstrate that BMP/SMAD-mediated Ephb4 expression requires the venous-enriched BMP type I receptor ALK3/BMPR1A. Together, our analysis demonstrates a requirement for BMP signalling in the establishment of Ephb4 expression and the venous vasculature.

AB - Venous endothelial cells are molecularly and functionally distinct from their arterial counterparts. Although veins are often considered the default endothelial state, genetic manipulations can modulate both acquisition and loss of venous fate, suggesting that venous identity is the result of active transcriptional regulation. However, little is known about this process. Here we show that BMP signalling controls venous identity via the ALK3/BMPR1A receptor and SMAD1/SMAD5. Perturbations to TGF-β and BMP signalling in mice and zebrafish result in aberrant vein formation and loss of expression of the venous-specific gene Ephb4, with no effect on arterial identity. Analysis of a venous endothelium-specific enhancer for Ephb4 shows enriched binding of SMAD1/5 and a requirement for SMAD binding motifs. Further, our results demonstrate that BMP/SMAD-mediated Ephb4 expression requires the venous-enriched BMP type I receptor ALK3/BMPR1A. Together, our analysis demonstrates a requirement for BMP signalling in the establishment of Ephb4 expression and the venous vasculature.

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KW - Bone Morphogenetic Protein Receptors, Type I/genetics

KW - Bone Morphogenetic Proteins/genetics

KW - Endothelial Cells/metabolism

KW - Gene Expression Regulation, Developmental

KW - Mice, Knockout

KW - Mice, Transgenic

KW - Receptor, EphB4/genetics

KW - Signal Transduction/genetics

KW - Smad1 Protein/genetics

KW - Smad5 Protein/genetics

KW - Transforming Growth Factor beta/genetics

KW - Veins/embryology

KW - Zebrafish/embryology

KW - Zebrafish Proteins/genetics

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SN - 2041-1723

VL - 10

SP - 1

EP - 18

JO - Nature Communications

JF - Nature Communications

M1 - 453

ER -

Venous identity requires BMP signalling through ALK3

Abstract

Keywords

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