Originally identified as protein regulators of cartilage and bone formation, bone morphogenetic proteins (BMPs) elicit additional functions during embryogenesis and morphogenesis of various tissues and organs. BMPs regulate growth, differentiation, patterning, chemotaxis, and apoptosis of various cell types and tissues, including mesenchymal, epithelial, hematopoietic, and neuronal cells. The spatial distribution and amount of BMP signaling are tightly regulated by a diversity of extracellular inhibitors, including Noggin, Chordin, DAN family members, and Crossveinless-2. However, extracellular regulation of BMP signaling has proven to be more complex than individual, specific inhibitors binding to BMP and inhibiting its ability to interact with its receptors.
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|CV-2 regulates BMP signaling to pattern vertebral bodies in the spinal cord and crossveins in the insect wing. High CV-2 levels within vetebral bodies in the spinal cord or crossveins in the fly wing prevent BMP signaling, while low levels at the boundaries promote signaling. BMP signaling activates transcription of CV-2 and this positive feedback helps sharpen the boundary between regions of high and low CV-2 expression.|
Crossveinless-2 (CV-2), also known as bone morphogenetic protein-binding endothelial cell precursor-derived regulator (BMPER), is a secreted protein containing five tandem chordin-like cysteine-rich domains and a partial von Willebrand factor type D domain.1, 2 Reports show that CV-2 directly interacts with BMP-2, -4, and -6 to antagonize BMP signaling, and CV-2 can block BMP signaling in both animal cap assays and in differentiating embryonic stem cells.2 In addition, human CV-2 can inhibit BMP-2- and BMP-4-dependent osteoblast differentiation and BMP-dependent differentiation of chondrogenic cells.1 Paradoxically, genetic data from Drosophila, biochemical experiments in COS7 cells, and analysis of organ phenotypes in CV-2 null mice suggest that CV-2 can also potentiate BMP signaling.3, 4, 5 Recently, these disparate findings were reconciled when the mechanism by which CV-2 functions was further described and refined.
During development of the Drosophila wing, a BMP gradient modulated by the short-range molecule CV-2, is required for proper crossvein formation.3 Using a combination of biochemical and genetic data, Serpe et al. showed that low CV-2 levels help deliver BMP to its receptor, while high CV-2 levels sequester BMP and antagonize signaling.6 This biphasic activity, along with positive feedback regulation of CV-2 by BMP signaling, results in sharp boundaries and gives rise to localized and distinct crossveins in the fly wing.6
In vertebrates, the impact of CV-2 on BMP signaling is also biphasic, although the molecular mechanism differs. Ambrosio et al. demonstrated that CV-2 interacts with Chordin to coordinate diffusion of BMP on the ventral side of the Xenopus embryo.7 When Chordin levels are low, CV-2 cooperates with Chordin to sequester BMP from its receptors.7 As Chordin levels increase, CV-2 switches from antagonizing BMP to antagonizing Chordin, thereby enhancing BMP signaling.7
Further investigation in CV-2 knockout mice revealed an interesting morphogenetic phenotype in the thoracic vertebrae. In mouse embryos, CV-2 is expressed in future vertebral bodies, while BMP-4, Chordin, and Chordin-like proteins are all expressed in the intervertebral disc region. In CV-2 null embryos, the vertebral bodies are reduced in size and the 13th thoracic vertebra displays a posterior homeotic transformation characterized by loss of the 13th rib.8 By looking at BMP signaling via Smad phosphorylation in this region, Zakin et al. determined that CV-2 is required to facilitate BMP signaling in the region adjacent to, but not within, the site of high CV-2 expression.8 Thus, it appears that CV-2 may help establish morphogenetic fields of BMP signaling resulting in discrete boundaries in mammalian vertebrae in much the same way as it does in the crossveins of insect wings.
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