Vertebrate crossveinless 2 is secreted and acts as an extracellular modulator of the BMP signaling cascade.

In vertebrates and invertebrates, BMP/Dpp (Bone Morphogenetic Protein/Decapentaplegic) signaling regulates the orchestrated processes of embryogenesis. Recent studies have revealed that BMP/Dpp signaling is controlled extracellularly as well as intracellularly. One extracellular regulatory molecule is the Chordin/Short gastrulation protein (Chordin/Sog), a secreted protein that acts as an antagonist to BMP/Dpp. Chordin/Sog contains four cysteine-rich (CR) domains that bind to and inactivate BMP/Dpp. In contrast, a positive regulator has been identified in Drosophila. Named crossveinless 2 (cv-2), this molecule contains five CR domains at the N-terminal half and a von Willebrand factor D domain at the C-terminal part. Genetic data suggest that Cv-2 potentiates Dpp signaling. We isolated chick and mouse CV-2 genes and found that CV-2 is secreted and enhances BMP signaling. Expression patterns were closely related to those of BMPs, supporting the likelihood of a tight link. Our data show for the first time that CV-2 is a conserved, positive regulator of BMP signaling and that CR domain proteins act as both positive and negative modulators of BMP signaling.