title: Crossveinless 2 is an essential positive feedback regulator of Bmp signaling during zebrafish gastrulation.
abstract: Signaling by bone morphogenetic proteins (Bmps) plays a pivotal role in developmental and pathological processes, and is regulated by a complex interplay with secreted Bmp binding factors, including Crossveinless 2 (Cvl2). Although structurally related to the Bmp antagonist Chordin, Crossveinless 2 has been described to be both a Bmp agonist and antagonist. Here, we present the first loss-of-function study of a vertebrate cvl2 homologue, showing that zebrafish cvl2 is required in a positive feedback loop to promote Bmp signaling during embryonic dorsoventral patterning. In vivo, Cvl2 protein undergoes proteolytic cleavage and this cleavage converts Cvl2 from an anti- to a pro-Bmp factor. Embryonic epistasis analyses and protein interaction assays indicate that the pro-Bmp function of Cvl2 is partly accomplished by competing with Chordin for binding to Bmps. Studies in cell culture and embryos further suggest that the anti-Bmp effect of uncleaved Cvl2 is due to its association with the extracellular matrix, which is not found for cleaved Cvl2. Our data identify Cvl2 as an essential pro-Bmp factor during zebrafish embryogenesis, emphasizing the functional diversity of Bmp binding CR-domain proteins. Differential proteolytic processing as a mode of regulation might account for anti-Bmp effects in other contexts.
authors.affiliation: Max-Planck-Institute of Immunobiology, Stuebeweg 51,79108 Freiburg, Germany.
authors.forename: Fabian
authors.initials: F
authors.lastname: Rentzsch
authors.forename: Jinli
authors.initials: J
authors.lastname: Zhang
authors.forename: Carina
authors.initials: C
authors.lastname: Kramer
authors.forename: Walter
authors.initials: W
authors.lastname: Sebald
authors.forename: Matthias
authors.initials: M
authors.lastname: Hammerschmidt
mesh_terms: D000818:Animals; D019521:Body Patterning / Q000235:genetics*; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D004625:Embryo, Nonmammalian / Q000378:metabolism; D004843:Epistasis, Genetic; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D005775:Gastrula / Q000166:cytology / Q000378:metabolism; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D015398:Signal Transduction; D015854:Up-Regulation / Q000235:genetics*; D015027:Zebrafish / Q000196:embryology*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D019485:Bone Morphogenetic Proteins; D020690:GTPase-Activating Proteins; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D029961:Zebrafish Proteins; C509801:crossveinless 2 protein, zebrafish; C054234:chordin