Venous identity requires BMP signalling through ALK3

Neal, A and Nornes, S and Payne, S and Wallace, M D and Fritzsche, M and Louphrasitthiphol, P and Wilkinson, R N and Chouliaras, K M and Liu, K and Plant, K and Sholapurkar, R and Ratnayaka, I and Herzog, W and Bond, G and Chico, T and Bou-Gharios, G and De Val, S (2019) Venous identity requires BMP signalling through ALK3. Nature Communications, 10 (1). ISSN 2041-1723

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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 venousspecific gene Ephb4, with no effect on arterial identity. Analysis of a venous endotheliumspecific 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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