BMPER is a conserved regulator of hematopoietic and vascular development in zebrafish

Abstract

For the proper development of vertebrate embryos as well as for survival of the adult organism, it is essential to form a functional vascular system. Molecules involved in this process are members of highly conserved families of proteins that exert conserved functions across species. Bone morphogenetic proteins (BMP) are extracellular factors that are regulated by extracellular modulators and bind to BMP receptors, which in turn activate intracellular signaling cascades. BMPs are necessary not only for induction of endothelial and hematopoietic lineages but also for further endothelial and hematopoietic cell differentiation. Previously, we identified BMPER (BMP endothelial cell precursor derived regulator) and demonstrated its spatiotemporal expression at sites of vasculogenesis and direct modulation of BMP activity. To directly investigate the role of BMPER in vascular development, we cloned the BMPER ortholog in zebrafish (zbmper). It is expressed at sites of high BMP activity, including vascular precursor cells located in the aortic arches and the intermediate cell mass during zebrafish embryonic development. Knockdown of zbmper results in a dorsalized phenotype, a reduced number of gata1 expressing hematopoietic precursor cells and of circulating blood cells as well as in a vascular phenotype. The generation of the caudal vein is compromised and the pattern guiding of the intersomitic vessels is disturbed, indicating that zbmper is required for early steps in vascular pattern formation and hematopoiesis in zebrafish.

Antagonism and synergy between extracellular BMP modulators Tsg and BMPER to balance blood vessel formation

“…Consistently, our Tsg deficiency data from zebrafish and HUVECs suggest that under these circumstances reduction of Tsg expression levels enhanced endothelial cell proliferation and sprouting by enhanced BMP signalling. On the contrary, BMPER morphants displayed a loss of CVP formation and in addition disturbed intersomitic vessel (ISV) growth (see also Moser et al, 2007) indicating loss of BMP signalling in the developing CVP. Of interest, in Tsg/BMPER double morphant embryos we observed less cyst formation compared to Tsg single morphants, suggesting that the cyst formation is caused by BMPER and enhanced BMP signalling in the absence of Tsg.…”

The extracellular regulation of bone morphogenetic protein signaling

“…But Cv2 proteins are not simple co-receptors, as they can also inhibit signaling. Cv2 regulates BMP signaling in early axis formation in Xenopus (Ambrosio et al, 2008), as well as axis formation, hematopoiesis and vascular development in zebrafish (Moser et al, 2007;Rentzsch et al, 2006), neural crest formation in chick (Coles et al, 2004) and skeletogenesis in mice (Ikeya et al, 2006;Ikeya et al, 2008;Zakin et al, 2008). But the direction of that modulation varies, even in contexts that appear homologous (e.g.…”

Crossveinless 2 regulates bone morphogenetic protein 9 in human and mouse vascular endothelium

“…5,10 MGP is induced by BMP-4 in ECs and antagonizes BMP-2, BMP-4, and BMP-7. 2,11 It inhibits angiogenesis through feedback inhibition of BMP-4, 9,12 and lack of MGP results in AVMs similar to ALK1 deficiency.…”

“…9,16 It is differentially expressed in endothelial precursor cells, and appears in that context to antagonize BMP signaling and EC differentiation. 10,17 However, it is not clear how CV2 antagonizes EC differentiation, or how it functionally relates to, or potentially overlaps with the function of MGP in the vasculature.…”