Research article

The Netrin-related domain of Sfrp1 interacts with Wnt ligands and antagonizes their activity in the anterior neural plate

Javier Lopez-Rios^{* 1,2} , Pilar Esteve^{* 1,3} , Jose Maria Ruiz^1,3 and Paola Bovolenta^1,3

¹Departamento de Neurobiología Molecular Celular y del Desarrollo, Instituto Cajal, CSIC, Dr. Arce 37, Madrid, 28002, Spain

²Developmental Genetics, DBM Centre for Biomedicine, University of Basel, Mattenstrasse, CH-4058, Basel, Switzerland

³CIBER de Enfermedades Raras (CIBERER), Dr. Arce 37, Madrid, 28002, Spain

author email corresponding author email* Contributed equally

Neural Development 2008, 3:19doi:10.1186/1749-8104-3-19

Published:	20 August 2008

Abstract

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 Sfrp1_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 β-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.