A novel SULF1 splice variant inhibits Wnt signalling but enhances angiogenesis by opposing SULF1 activity

The importance of SULF1 in modulating the activities Of multiple signalling molecules is now well established. Several studies, however, reported little or no effect Of SUM null mutations, questioning the relevance of this gene to in vivo development. The failure of SULF1 deletion to influence development may be predicted if one considers the involvement of a naturally Occurring SUM antagonist, generated by alternative splicing of the same gene. We demonstrate that while the previously described SUM (SULF1A) enhances Wnt signalling, the novel shorter isoform (SULF1B) inhibits Writ signalling. Our Studies show developmental stage specific changes in the proportions of SULF1A and SULF1B isoforms at both the mRNA and protein levels in many developing tissues, with particularly pronounced changes in developing and adult blood vessels. Unlike SULF1A, SULF1B promotes angiogenesis and is highly expressed in endothelial cells during early blood vessel development while SULF1A predominates in mature endothelial cells. We propose that the balance of two naturally occurring SUM variants, with opposing functional activities, may regulate the overall net activities Of multiple secreted factors and the associated signalling cascades essential for normal development and maintenance of most tissues. Crown Copyright (C) 2009 Published by Elsevier Inc. All rights reserved.