ZFIN ID: ZDB-PUB-060130-9
Crossveinless 2 is an essential positive feedback regulator of Bmp signaling during zebrafish gastrulation
Rentzsch, F., Zhang, J., Kramer, C., Sebald, W., and Hammerschmidt, M.
Date: 2006
Source: Development (Cambridge, England)   133(5): 801-811 (Journal)
Registered Authors: Hammerschmidt, Matthias, Rentzsch, Fabian
Keywords: Zebrafish, Crossveinless 2, Bmp
MeSH Terms:
  • Animals
  • Body Patterning/genetics*
  • Bone Morphogenetic Proteins/genetics
  • Bone Morphogenetic Proteins/metabolism*
  • Embryo, Nonmammalian/metabolism
  • Epistasis, Genetic
  • GTPase-Activating Proteins/genetics
  • GTPase-Activating Proteins/metabolism*
  • Gastrula/cytology
  • Gastrula/metabolism
  • Glycoproteins/genetics
  • Glycoproteins/metabolism
  • Intercellular Signaling Peptides and Proteins/genetics
  • Intercellular Signaling Peptides and Proteins/metabolism
  • Mutation
  • Signal Transduction
  • Up-Regulation/genetics*
  • Zebrafish/embryology*
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
PubMed: 16439480 Full text @ Development
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.