LÓPEZ-RÍOS MORENO, JAVIER, Esteve, Pilar , Ruiz, Jose Maria , Bovolenta, Paola
Si
Neural Dev.
Article
Científica
3.452
3.508
20/08/2008
000259455800001
Background: Secreted frizzled related proteins (SFRPs) are multifunctional modulators of Wnt and BMP (Bone Morphogenetic Protein) signalling necessary for the development of most organs and the homeostasis of different adult tissues. SFRPs fold in two independent domains: the cysteine rich domain (Sfrp(CRD)) related to the extracellular portion of Frizzled (Fz, Wnt receptors) and the Netrin module (Sfrp(NTR)) defined by homologies with molecules such as Netrin-1, inhibitors of metalloproteinases and complement proteins. Due to its structural relationship with Fz, it is believed that Sfrp(CRD) interferes with Wnt signalling by binding and sequestering the ligand. In contrast, the functional relevance of the Sfrp(NTR) has been barely addressed. Results: Here, we combine biochemical studies, mutational analysis and functional assays in cell culture and medaka-fish embryos to show that the SfrpI(NTR) mimics the function of the entire molecule, binds to Wnt8 and antagonizes Wnt canonical signalling. This activity requires intact tertiary structure and is shared by the distantly related Netrin-1(NTR). In contrast, the Sfrp1(CRD) cannot mirror the function of the entire molecule in vivo but interacts with Fz receptors and antagonizes Wnt8-mediated beta-catenin transcriptional activity. Conclusion: On the basis of these results, we propose that SFRP modulation of Wnt signalling may involve multiple and differential interactions among Wnt, Fz and SFRPs.