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




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Neural Development

, 3:19

First Online: 20 August 2008Received: 28 February 2008Accepted: 20 August 2008

Abstract

BackgroundSecreted 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 SfrpCRD related to the extracellular portion of Frizzled Fz, Wnt receptors and the Netrin module SfrpNTR 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 SfrpCRD interferes with Wnt signalling by binding and sequestering the ligand. In contrast, the functional relevance of the SfrpNTR has been barely addressed.

ResultsHere, we combine biochemical studies, mutational analysis and functional assays in cell culture and medaka-fish embryos to show that the Sfrp1NTR 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-1NTR. In contrast, the Sfrp1CRD cannot mirror the function of the entire molecule in vivo but interacts with Fz receptors and antagonizes Wnt8-mediated β-catenin transcriptional activity.

ConclusionOn the basis of these results, we propose that SFRP modulation of Wnt signalling may involve multiple and differential interactions among Wnt, Fz and SFRPs.

AbbreviationsCRDCysteine-rich domain

EEmbryonic day

FzFrizzled

HAHaemagglutinin

MoMorpholino

NTRNetrin-related motif

SFRPSecreted frizzled related protein

BMPBone morphogenetic protein: PMSF: Phenylmethylsulphonyl fluoride.

Electronic supplementary materialThe online version of this article doi:10.1186-1749-8104-3-19 contains supplementary material, which is available to authorized users.

Javier Lopez-Rios, Pilar Esteve contributed equally to this work.

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Autor: Javier Lopez-Rios - Pilar Esteve - Jose Maria Ruiz - Paola Bovolenta

Fuente: https://link.springer.com/



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